Dietary Fibre for Use in the Treatment of a Gastro-Intestinal Side-Effect of a Nutrition or Medicament

ABSTRACT

The invention relates to a dietary fibre for use in delaying or otherwise reducing a sating effect of a medical nutrition or of a medicament, wherein the medical nutrition or medicament is for oral or gastro-enteric administration by a human. The invention further relates to a method for prophylactically or therapeutically treating a human in need thereof, the treatment comprising administering an effective amount of a dietary fibre, in combination with a pharmaceutical composition or a nutrition as defined in any of the preceding claims, thereby reducing a sating effect of the pharmaceutical composition or the nutrition. The invention further relates to products suitable for use in such a method.

The invention relates to dietary fibre for use in a treatment of asubject that suffers from an undesired side-effect of a nutrition, anutritional product or a medicament. Further, the invention relates to anutrition, a nutritional product and to a medicament. Further, theinvention relates to a product for use in the treatment ofmalnourishment.

Various medicaments are known to cause negative gastro-intestinalside-effects, such as nausea, loss of appetite, vomiting, excessivesatiety, inactive action and peristalsis of the gut or abdominal cramps.Examples of such medicaments are opiates, selective serotonine re-uptakeinhibitors (SSRI's) and chemotherapeutics. Apart from beingdiscomforting to the subject, such effects may impair consumercompliance.

In addition, medical nutrition, when designed inappropriately or whencomprising high amounts of otherwise healthy nutrients, may give rise tosimilar undesired gastro-intestinal side-effects, whereby consumercompliance is relatively poor. As a result thereof (voluntary) intake isimpaired, which decreases the overall benefit of administration of thefood product. In particular highly concentrated liquid formulae (orsolid nutrition or tube feeding which is administered at too high ratemay cause nausea or be experienced by consumers as too filling (heavy),whereby less of the nutrition is consumed than is desired in order toprovide sufficient nourishment.

In WO 2005/002588 it is observed that a pharmaceutical provided with anenteric coating can provide improved pharmaceutical activity withreduced adverse side effect such as nausea. For example, the bicyclic13,14-dihydro-16,16-difluoro-prostaglandin E1 had less side effect ofnausea when delivered by enteric coated capsules produced by sprayinghydroxypropyl Me cellulose phthalate as enteric coating. It is apparentthat the cellulose derivative is used herein to control release of thepharmaceutically active compound.

It is a drawback that the product needs to be coated in order to reducea side effect, as the process of coating makes the process of making theproduct more complex. In addition, although enteric coatings are oftenused for pharmaceuticals, it is not an approach that would generally beconsidered to be useful for nutrition; a dosage of nutrition isgenerally much bulkier than a pharmaceutical dosage. Moreover, at leastfor orally ingested nutrition, coating the nutrition may affectorganoleptic properties (such as loss of taste, change in mouth feel),which may have a detrimental effect on the liking of the product andimpair food compliance. In addition coated nutrients typically loosecoating integrity under the conditions used for manufacture ofheat-treated homogeneous liquid formula

WO 97/28700 relates to a nutrient composition for use during exerciseand aims to overcome problems associated with the ingestion ofcarbohydrates resulting in a blood glucose peak shortly after ingestion;along with a concomitant peak in blood insulin. It is observed in WO97/28700 that this is then followed by an equally rapid drop in bloodglucose levels, even to levels below normal range. Such reactivehypoglycaemia causes unpleasant symptoms, like fatigue and reduceexercise performance.

Further, fatigue may rapidly set in; greatly reducing exerciseperformance. A nutrient composition designed to avoid these problemswhilst maintaining raised blood glucose levels is disclosed, whichcontains carbohydrate and a source of soluble fibre, especially afibre-rich cereal. This document does not relate to increasing satietyor decreasing nausea as caused by medicaments or medical nutrition.

It is an objective of the present invention to provide a product for usein a prophylactic or therapeutic treatment of a negativegastro-intestinal side-effect a medicament or of medical nutrition,wherein preferably consumer compliance is increased.

It is another objective of the invention to increase voluntary foodintake, shorten the period between surgery and the moment thatvoluntarily oral food intake can be started, prevent the need to changeover from sip feed to oral feeding of enteral or parenteral tubefeeding, improve recovery after trauma, decrease length of stay inhospitals, decrease secondary complications after trauma, and/ordecrease low appetite, nausea, after medication.

The inventors found that one or more of these objectives is realised byproviding a specific component, to a subject using medical nutrition ora medicament.

Accordingly, the present invention relates to dietary fibre, for use inprophylactically or therapeutically treating a negative gastro-entericside-effect of a composition, preferably a medical nutrition or amedicament, wherein the medical nutrition or medicament is for oral orgastro-enteric administration by a human. An example of the latter wayof administration is a drink feed or tube feeding into the stomach.

The inventors realised in particular that administration of specificmedical nutrition or a medicament such as an SSRI, a monoamine oxidase(MAO) inhibitor, an opiate or a chemotherapeutic agent, can give rise toa undesired side-effect as a result of an interaction between thenutrition or medicament in the stomach or the proximal part of theintestines, more in particular in the stomach, duodenum, jejunum, and/orthe proximal part of the ileum.

Without being bound by theory, the inventors consider that medicalnutrition or a specific medicament can give rise to an undesiredside-effect as a result of overstimulation of sensing cells in theintestines. These sensing cells induce a neuro-endocrine response to(changes in) the luminal contents of stomach or intestine. This responsewhen proper is useful to aid digestion, prepare for the microbialcondition in the lumen, to prevent damage to the gut tissue and allowefficient absorption of nutrients. However, overstimulation inducescramps, diarrhea and other gastrointestinal discomfort. For instancesensing cells may release a pattern of neurotransmitters andneuropeptides dependent on the intraluminal circumstances. In particularenteral administration of nutrition or a medicament into thegastro-intestinal tract can invoke a response by the sensing cells as aconsequence of intraluminal circumstances, such as stretch, ‘physical’pressure (stretch due to changes in internal volume), acidity, osmoticvalue (e.g. high ionic strength of the contents of the intestine),distortion and shearing forces and the presence of pungent components oractivating substances, such as receptor agonists, specific proteins orpeptides, specific lipids and fatty acids. Entero-endocrine cells (EEcells) and enterochromaffin cells (EC cells) are particularly sensitivein this respect and are widely expressed in the gut and especially inthe proximal parts of the small intestine. EC cells are capable ofreleasing serotonin as an important member of the total neuro-endocrineresponse and this released serotonin is thought to be of particularimportance in themodulation of the response of the gastrointestinalsystem and the systemic serotonin concentrations by consumption of anutritional product or medicament. The enteric nervous system (ENS) isan important modulator of the neuroendocrine response. A part of this isthe nervus vagus. It is the inventors understanding that a medicalnutrition may in particular give rise to overstimulation of sensingcells, due to a ‘highly filling property’, a high energy density, itsrheological consistency, a high dry matter content, a high acidityand/or a high buffer strength or capacity.

For a medicament, it is contemplated that it is in the nature of certainactive components, such SSRI's and others mentioned herein, that sensingcells In the gastrointestinal tract become stimulated after oral intakeof these medicaments and trigger a sating neuro-endocrine response.

Accordingly, the invention in particular relates to a dietary fibre foruse in avoiding or reducing an overstimulation of the proximal parts ofthe small intestine, preferably of the duodenum and/or jejunum, inparticular an overstimulation of sensing cells, preferably EC cells inthe small intestine, preferably in the duodenum and/or jejunum. Aneffect of such use is in particular reducing, optionally to the extentthat its occurrence is avoided, a gastro-intestinal side-effect, asmentioned elsewhere in the present disclosure.

It is noted that a role of dietary fibre in the functioning of thegastro-intestinal tract has been a topic of major scientific interestfor a considerable period of time. However, the attention is generallydrawn to a role of dietary fibre in the colon by modulating the growthof colonic bacteria. Dietary fibre is generally not considered to bebiologically active in the smaller intestine other than potentiallyaffecting local viscosity and rate of absorption of nutrients. Asignificant effect on EC cells in the proximal part of the intestines isthus unexpected.

In a particularly preferred embodiment, the invention relates to adietary fibre for use in delaying or otherwise reducing nausea or asating effect of a composition, preferably a medical nutrition or of amedicament, wherein the composition, such as the medical nutrition ormedicament, is for oral or gastro-enteric administration by a human.

The sating effect of a medicament or medical food can be established byapplying the guidelines as described in Blundell et al, Obesity Rev2010, 11, 251-270. It can be determined in various ways, e.g. byinterviewing and individual or measuring ad libitum food consumption ofthe experimental food. A method is selected which is capable ofmeasuring that the inclusion of the fibre component in a productdecreases the sating properties of the original product. It is importantto notice that the sating properties of a product become evident brieflyafter consumption and last for a period of 1 to 5 hours. The time ofmeasurement is important. For measuring sating properties on shorterterm, i.e. within 1.5 hours after consumption, measurement ofneuro-endocrine response is preferred, while for measurement of longerterm effects, interviews are preferred by the inventors. Examples ofsuitable biomarkers for the neuro-endocrine response are theconcentration of one or more peptides, like CCK, PYY 3-36), GLP-1,amylin or ghrelin, or of neurotransmitters, like serotonin and/or itsmetabolites. Alternatively the activity of the gut tissue (motility) orENS can be measured.

Alternatively one can measure the amount of a standard food that isconsumed on a voluntary base in the period 15 minutes to 3 hours afterhaving consumed the first product. The latter amount is preferablyexpressed as the amount of energy (kJ) that is consumed.

The inventors consider that the invention is in particular suitable forreducing a sating effect, as a side effect of an overstimulation ofsensing cells, preferably EC cells, in the small intestine. It is inparticular surprising that a dietary fibre is suitable for reducing asatiety effect of a composition such as a medical nutrition or of amedicament. Dietary fibre has been reported in the art as having asating effect. For example WO2008/066308 discloses a nutritional productcomprising glucomannans, whey proteins and soy protein isolate to inducesatiety. The anorexic effect is suitable for letting people lose weight.This is contrary to what is desirable for many patients which sufferfrom malnourishment, like many hospital patients and elderly.

In a further preferred embodiment, the invention relates to a dietaryfibre for use in alleviating or avoiding nausea, reducing loss ofappetite (optionally to the extent that the loss is avoided), orreducing vomiting urges (optionally to the extent that such urges areavoided), experienced after oral or gastro-enteric intake of acomposition, preferably a medicament or medical nutrition.

In a further preferred embodiment, the invention relates to the use ofdietary fibre for increasing consumer's compliance to consuming theprescribed dose, in particular to consuming the ready to use dose unitof a composition, preferably being a medical nutrition or a medicament.In a further embodiment the invention relates to increasing overall foodintake, by increasing the intake of the product, and/or by increasingnet intake of food over the same day.

In a preferred embodiment, an individual who is malnourished or is atrisk of becoming malnourished and experiences adverse effects whenconsuming normal or inappropriately designed nutritional products istreated with a nutritional product according to the invention. In apreferred embodiment a product according the invention is used for(improving the) treatment of malnourishment.

Malnourishment in one or more nutritional components is a frequent andinternationally recognized problem, especially in aged and diseasedindividuals, despite the availability of many kinds of food products.This has a major impact on the persons health, recovery rate and oncosts of the society (Freijer, 2012, 2013 andhttp://www.guardian.co.uk/social-care-network/2013/may/29/malnutrition-older-people-lack-of-food.andhttp://www.nutraingredients.com/Research/Malnutrition-in-hospital-Avoidable-but-not-a-priority

Malnourishment is especially prevented or treated and health is inparticular improved when the individual is compliant to food protocolsand is starting as soon as possible after discovery of malnourishment ortrauma (like surgery).

Malnourishment is especially in issue when absorption from gut lumen isimpaired or when the individual experiences a cancer or inflammation

In a specific embodiment, the dietary fibre is used for increasing earlyintake of food after surgery.

The dietary fibre—when administered to a human subject—may in particularbe a dietary fibre that has an ameliorating effect on theneuro-endocrine response and/or the amount of serotonin that is releasedby the enterochromaffin cells and/or enteric nervous system in the smallintestine as a reaction to the postprandial luminal contents.

The dietary fibre may modulate the human microbiota as occurs in thesmall intestine, which may include bacteria, archae, moulds and yeasts.In particular after oral or gastro-enterical administration ofappropriate amounts of the dietary fibre or the product wherein thedietary fibre for use as an active ingredient in accordance with thepresent invention (the ‘active fibre’) is included, the type andactivity of bacteria and archaea change, which inhabit the proximalpart, more in particular those that inhabit the mucosa of duodenum,jejunum and proximal parts of the ileum. The changed microbiota in thesmall intestine may also induce a better symbiosis between genera in thesmall intestine, and between host epithelial cells and mucosal microbialspecies. This may be reflected by a higher rate of synthesis or releaseof zwitter-ionic polysaccharides from locally present bacteria. Anexample of such polysaccharide is the polysaccharides that aresynthesized by Bacteroidetes genera, in particular Polysaccharide A2. Ina specific embodiment the product increases or normalizes the presenceor activity of Bacteroides fragilis. In one embodiment the productincreases the presence of Bacteroidetes in or near the mucosa of thesmall intestine, in particular that of Bacteroides fragilis. It isobserved that the polysaccharide as synthesized by the bacteria in thegut differs in chemical structure and identity from the polysaccharidesthat can be isolated from herbs like Echinacea, as disclosed in U.S.Pat. No. 4,857,512, though these polysaccharides may be included incertain embodiments of the invention.

In an embodiment the amount or activity of Sutterella genera as presentin or near the ileal mucosa may decrease, as can be measured bydetermining species-specific RNA (e.g. the 16S rRNA) in a representativesample.

In an embodiment, the dietary fibre supports the development of thosearchaeon genera, which facilitate the colonisation of useful bacteria inthe mucosa of the duodenum and proximal parts of the ileum. Thesearchaea in the duodenum and ileum, and in the mucosa in these parts ofthe small intestine may differ from known colonic archeae, and frommethanobrevibacter genera, as disclosed in e.g. WO2006102350. Thesymbiosis between archaea and mucosal bacteria is thought to be mediatedby the secretion of adhesion modulating substances, glycolipids andpolysaccharides that are released by archaea. The net effect of thesechanges may be the lower release of serotonin of locally present neuronsand enterochromaffin cells, a decreased activation of the local entericnervous system and/or a decreased degree of activation by the vagusnerve.

The presence of a more diverse and adapted community of microbiota inthe proximal parts of the small intestine facilitates efficientfermentation of dietetic fibres in more distal parts of the gut. Thepresence of a greater variety in metabolic capacity e.g. by the presenceof specific E. coli or Bifidobacteria variants may result in an earlythough partial hydrolysis of dietetic polysaccharides into (smaller)oligosaccharides. The smaller sized oligosaccharides are easier toaccess by other microbial enzymes, e.g. by hydrolases or feruloylesterases, for example those originating from or present in symbioticmicroorganisms. This allows generation of a different profile and widediversity of fermentation products. These fermentation products mayinclude for example ferulic acid, monosaccharides and small organicmolecules which can interact with receptors on the membranes ofepithelial cells or microbes. The active community of microbes in themucosa also induces a higher expression of epithelial “brush border”di-saccharidases and hexose transporters, which facilitates absorptionand use of nutrients from the intestinal lumen. The changed microbiomein the small intestine also decreases the amount of interferon-gammathat will be released as a result of luminal contents, which is thoughtto contribute to the lower activation of EC cells after administrationof the product of the invention.

It is thought that after consumption of a product in accordance with theinvention, a more stable mucous layer is produced, which remains at thesame location due to the lower degree of stimulation of the sensingcells, and which is not degraded by intestinal excess serotonergicactivity or due to diarrhoea, and which is not degraded excessively byintestinal microbes, like Akkermansia muciniphila, as is the case withprior art products which are used to promote central serotonergicsystems.

The fibre fraction may serve, at least for a part, as a nutrient formicroflora in the small intestine. To the extent that the fibre fractionreaches a specific part of the intestine, the fibre fraction willtypically induce a change in the microflora in that part of theintestines. This change can be measured by proper sampling and analyzingof representative samples of mucosa or luminal contents of that part ofthe intestines, including the proximal parts of the small intestine.

When referring herein to a treatment, this generally includesprophylactic treatments and therapeutic treatments, unless specifiedotherwise. A prophylactic (preventive) treatment generally is aimed atreducing the chance that the treated subject develops a trait,impairment, symptom, disease, syndrome or disorder. The effectiveness ofa prophylactic treatment can e.g. be determined by comparing theprobability that a specific trait, impairment, symptom, disease,syndrome or disorder develops in a sufficiently large and representativegroup of subjects or animals and in a double blind placebo controlledstudy, designed according the principles of Good Clinical practices,wherein one part of the group is treated according to the invention andanother part is treated with a placebo for a relevant period of time.The skilled person will be able to define suitable conditions for thestudy, depending on the intended effect.

The term “a” or “an” as used herein is defined as “at least one” unlessspecified otherwise.

When referring to a noun (e.g. a compound, an additive etc.) in thesingular, the plural is meant to be included.

The term “or” as used herein is to be understood as “and/or” unlessspecified otherwise.

When referred herein to a product in relation to the invention, thisgenerally refers to a nutritional composition, a medicament, acombination of dietary fibre claimed as such or claimed for a use inaccordance with the invention.

When referred herein to the ‘total fibre fraction’ (TFF) this generallymeans the total of matter formed by dietary fibre. This includes thedietary fibre that is present as an active ingredient in the product,and that it is effective in contributing to an intended use of theinvention (the ‘active fibre’) and other dietary fibre which does nothave an effect on a claimed use, but may still have a dietary role. Forinstance additional fibres having no significant role in the smallintestine can be included for technological or organoleptic reasons orto modulate colonic events. e.g. it can serve as a bulking fibre (e.gcellulose)) or may induce envisaged colonic events. The inclusion ofdietary fibre can be derived from the label of a commercial product orcan be analyzed by selecting an accepted method as known in the art asfor example has been disclosed in US 2010/0317573.

In the present disclosure, indigestible carbohydrates having a degree ofpolymerisation of 3 or more mono-saccharides are considered to be partof the dietary fibre fraction, independent whether they are soluble ornot or fermentable or not.

When the total fibre fraction comprises at least three, preferably atleast four different fibre ingredients, the fibre blend is called amultifibre blend (MF). Multifibre blends can comprise natural fibreingredients which are commonly consumed in the diet of a healthy person.

With respect to the active fibre, these may in particular be selectedfrom hemicelluloses, xylans, arabinoxylans and derivatized xylans, whichmay be synthetic or substituted (arabino) xylans from natural sources.

The ‘fibre ingredient’ is the ingredient that is used to include theactive dietary fibre in the manufactured nutrition, nutritional productor ready to use medicament. It does not need to be a chemically purecompound. A much preferred fibre ingredient is cereal bran, inparticular rice bran, either in raw form after physical separation ofthe starchy endosperm, or in more purified or processed forms, asexplained later in this document.

Mode of Action, Clinical Effects

The mode of action (MOA) can be multiple and depend on conditions andtiming and patient as well. Apart from an effect on 5HT release of ECcells the inventors consider in particular to be important: 1/modulation of expression patterns of serotonergic receptors overtissues, neurons and microbiota, 2/ modulation of expression anddistribution over the same type of cells, 3/ decrease of degree ofpostprandial stimulation of pre-synaptic 5HT1B receptors, 4/ decrease ofactivation of the neurons in the myenteric plexus, 5/ decrease of numberof sensing cells in the lamina propria, 6/ increase of orexigenicpathways by a decrease of postprandial release ofcorticotrophin-releasing hormone in the paraventricular nucleus of thehypothalamus or an increase and activation of the brain-reward system byactivation of the relevant neurons in the nucleus accumbens andstriatum, 7/ stimulation of co-release of dopamine and serotonin fromthe medial and lateral hypothalamus or 8/ by other mechanisms.

In an embodiment, the invention is in particular suitable to induce aselective way of modulating serotonin signalling, but without inducingexcessive serotonin—induced signalling of the enteric nervous system(ENS). In particular excessive serotonin release by the enterochromaffincells and ENS neurons is prevented, especially in the proximal parts ofthe gastro-intestinal tracts (GIT).

It is the inventors' finding that the fibre for use in accordance withthe invention in particular has an effect that can contribute to theeffect on serotonin. Further, a preferred product according to theinvention contributes to keeping the concentration of free serotonin inthe blood plasma relatively low. In particular, in an advantageousembodiment the fibre will promote the action of the serotonintransporter (SERT) as expressed on platelets which keeps theconcentration of free serotonin in blood plasma relatively low.

A fibre, combination or composition used in accordance with theinvention can in particular contribute to changing the expression ofserotonin receptors over tissues and/or changes the distribution andlocalization of the receptors per cell. A product according to theinvention also changes the degranulation and serotonin releasecharacteristics of serotonergic neurons, preferably in the entericnervous system, and EC cells. Without wanting to be bound by theory,this change can be mediated by an effect of the product on the activityof the nervus vagus, including the activity on cholinergic transmission.Administration of the product according the invention will induce asecretion of serotonin that is sufficiently low to prevent excessivesynergistic action with the cholecystokinine (CCK) that is released byconsumption of the food and prevents over-activation of the satingsystems in the brain, e.g. as modulated through the nervus vagus (NV).Alternatively or in addition the effect on the serotonin systems may bemediated by a decreased action of bile acids on the lining of the smallintestine or a modulation of the composition of the mucosal microfloraand the response of the enterocytes, EC cells, enteroendocrine cells anddendritic cells, on microorganisms. This changed response may include anincrease of the response of tolerizable genes, for example those thatoccur in macrophages inhabiting the small intestine or microglia, andare essential for a proper response after repeated exposure tomicroorganisms which induce the release of pro-inflammatory cytokineslike IL-6. Some of the relevant genes have been disclosed in Foster etal, 20078, Nature, 447, 972-978 and include the Hdc, Mmp13, Serpine 1,Edn1, Cspg2, Lipg and 116.

In one or more of these manners the administration of the productaccording the invention changes the functioning of the serotonergicsystems, for example in terms of the release characteristics, thesensitivity to endogenously released 5-HT, the characteristics of theresponse and the desensitization characteristics. The inventors inparticular contemplate, that thus, the invention is suitable to delay orotherwise delay nausea and/or satiety effects. It should be noted thatserotonin plays a direct or indirect role in the satiety centre in thebrains.

In principle, any male or female human may benefit from the use of adietary fibre in accordance with the invention that is treated withmedical nutrition or a medicament. In a specific embodiment, the fibreis for use in an individual that suffers from malnourishment, or ahospital patient, an institutionalized patient and elderly person, anoncology patient, a person that is subjected to chemotherapy orradiotherapy, or a person experiencing inflammatory processes. Thelatter can be determined by measuring blood values of cytokines as knownin the art or by medical diagnosis.

Serotonin receptors are currently considered to be a group of 7 types ofproteins. Each has its own distribution in the human body. Class 1serotonin receptors are predominantly expressed in the central nervoussystem and not in the gastrointestinal tract (GIT), while e.g. class 2and 3 serotonin receptors to an important extent determine the action ofthe serotonergic system in the gastrointestinal tract.

Fibre Fraction

The total fibre fraction in the nutritional product according theinvention preferably comprises fibre selected from the groups ofmodified and unmodified cereal fibre.

The product according the invention comprises a dietary fibre which ispreferably derived from a cereal. It can be isolated as such, or bemodified by chemical means to improve technological properties. Theinclusion of unmodified fibre is preferred.

In particular, the dietary fibre ingredient in the product may comprisefibre selected from the group of unmodified or modified cereal fibre. Apreferred fibre ingredient is a cereal bran. In an embodiment the brancomprises parts of the germ and is preferably relatively poor indigestible carbohydrates originating from the grain's endosperm andrelatively poor in the grain's husk as specified below.

In a different embodiment the ingredient comprises other parts of thegrain like proteins and lipophilic substances, as they occur in thecereal grain, as explained below.

Examples of suitable cereal grains include rice, barley, wheat, rye,oats, corn, amaranth, millet, quinoa and triticale.

In a preferred embodiment the fibre ingredient is rice bran. The branmay in particular be provided in combination with rice germ.

In a further embodiment the fibre ingredient is isolated from the grainsof Oryza sativa, Oryza glaberrima or Oryza nivara or cross-bredvarieties of these species. It is most preferred to isolate the fibrefrom a Oryza sativa variety.

The dietary fibre content of the fibre ingredient, preferably is atleast 10 wt. % of the fibre ingredient, in particular at least 15 wt. %.The dietary ingredient may substantially consist of dietary fibremolecules, but substantial amounts of other ingredients may be present.Thus, the dietary fibre content in the fibre ingredient can be less than50 wt. %, in particular 40 wt. % or less, or 35 wt. % or less

In a preferred embodiment the amount of aleurone-derived fibre is low.In a specific embodiment, also the amount of endosperm that isco-isolated is low, which is reflected by a low amount of digestiblecarbohydrates in the fibre ingredient. The proper fibres can be isolatedfrom the cereal grain by applying a combination of methods on the rawingredient, which are as such known in the art and can include grinding,sieving, extraction, steam treatment, alkali treatment and fermentation.Preferably this amount is less than 36 weight % (=wt %), more preferably20-32 wt % of the fibre ingredient. The amount of protein in the fibreingredient may in particular be in the range of 12-22 wt. %, preferably12-16 wt % of the fibre ingredient. Also lipids may be present in thefibre ingredient, in particular to an extent of 14-24 wt % of the fibreingredient. These amounts assume a moisture content of about 5 wt % ofthe ingredient. The concentrations of all components in the ingredientdrop proportionally with its moisture content, while the propertiesremain the same when used in the manufacture of a liquid formula asthose according the invention. The man skilled in the art canrecalculate the amount of components to a moisture degree of 5% in orderto establish whether a third party operates within the scope of thisinvention. Part of these cereal derived lipids, nitrogenous compoundsand digestible carbohydrates are caught in the fibre structures asisolated from the grain and remain there to a characteristic andrelevant extent during the manufacturing process of products accordingthe invention. The lipids that can be extracted from the fibreingredient can comprise lipophilic substances as occur naturally in thegrain, e.g. isoprenoids.

A suitable fibre can be isolated from the cereal grain by applying acombination of methods to the raw ingredient, which as such are known inthe art. They can include grinding, sieving, extraction, steamtreatment, alkali treatment and fermentation. Several combinations ofprocess steps have been used by different suppliers, though the finalmethod for isolating the fibre according the invention is specific. In apreferred embodiment the active fibre constituents are isolated byapplying a treatment at alkali pH or an extraction at alkali pH. This isapplied to remove residual digestible carbohydrates.

Preferably the fibre ingredient as isolated from cereal grain comprisesmore than 45 wt % hemicelluloses, based on the total dietary fibrecontent in the fibre ingredient. Parts of the cellulose and ligninspresent in the grain can be co-isolated, though the content of the sumof both in the fibre ingredient is less than 60 wt %. Preferably theweight ratio of hemicellulose fibres to fibres that are considered ascellulose or lignin is more than 0.3, preferably 0.5 to 3, mostpreferably 0.6 to 2.

In a preferred embodiment at least 10 wt %, more preferably more than 40wt %, most preferably 45-92 wt % of the dietary fibre in the fibreingredient is soluble in pure water at 20 degrees Celsius, whendissolved in an amount of 1 wt/vol %.

In a specific embodiment, more than 18 wt % of the fibre fraction isinsoluble under these conditions.

The grains can be dehusked and grinded and most of the starches removedin conventional ways to isolate a fraction that is relatively rich infibres compared to the intact grain. The solubility of these rawcereal-derived fibres can be improved by treatment with one or morehydrolyzing enzymes that are selective for the carbohydrates, and/orother components that are present in the raw cereal fibre.

Alternatively, the cereal fibres can be obtained from a raw cerealmaterial that is subjected to a fermentation process by exposing aslurry of the raw material comprising cereal fibres in water to one ormore organisms or enzymes. A suitable fermentation process includessubjecting the fibre to the enzymes of an Aspergillus species.Fermentation processes for cereals are known in the art and help inimproving solubility, by decreasing the molecular weight of thepolysaccharides that form the indigestible part of the carbohydrates. Aside effect is that the amount of digestible carbohydrates in the cerealfibre ingredient decreases. The half-product thus formed can besterilized to inactivate enzymes or kill the living microorganism. Aftersubsequent purification steps, which are known in the art, a fibreingredient is obtained that is suitable for use in accordance with theinvention.

In particular, the dietary fibre in the fibre ingredient may be composedfor at least 11 wt. % of xylans, preferably about 13 to about 80 wt % ofthe fibre fraction.

Preferably the xylans are hetero-saccharides, which are defined as beingthose oligomers or polymers of xylose that are substituted for more than4 wt % with saccharides other than xylose. These hetero-xylans includearabino-xylans (AX). In one preferred embodiment the arabino-xylans arebranched, which ensures the formation of non-linear molecules. Thearabinose substituents may make up 0.05 to about 1 times the amount ofxylose in the fibre. Part of the xylans may be (arabino)glucuronoxylans(AGX), glucuronoxylans or (glucurono)arabinoxylans (GAX), using theterminology of Ebringerova, et al, in Adv Polym Sci, 2005, 186, 1-67.The sum of AGX and GAX may be 0.4-30 times the amount of purearabinoxylans. In one embodiment the amount of AGX is 0.5 to 24 timesthe amount AX.

The xylose moieties in the non-digestible carbohydrate fraction of thefibre ingredient may also be substituted with monosaccharides other thanarabinose, like uronic acids, methylated uronic acids, fucose andgalactose.

One or more of the monosaccharides that are linked to the xyloseoligomer may be substituted with phenolic compounds like ferulic acid.In a preferred embodiment the amount of ferulic acid in the fibreingredient is 0.1 to about 6%. After oral administration of the producta major part of the ferulic acid will be released in the intestine, evenin proximal parts of the small intestine, by the action of intestinalenzymes, e.g. those bound to or originating from microorganisms.

In an embodiment, the xylans from the grain have been partiallyhydrolysed prior to inclusion in the product in order to improvesolubility in the ready to use product and to improve microbial use inthe proximal part of the gut and increase the efficacy of the product. Asuitable degree of hydrolysis (DH) is 2 to 10. This can be achieved byapplying an alkali treatment, an enzymatic hydrolysis or a fermentationprocess to the fibres of the grain. In a preferred embodiment theenzymatic process includes a hydrolysis by a xylanase. Suitable sourcesof xylanase which are capable of hydrolysing cereal xylans are known inthe art. In a preferred embodiment the fermentation step includes a stepwherein the cereal fibre material is subjected to fermentation by alactobacillus or a combination of a lactobacillus with yeast andoptionally other microorganisms.

As already mentioned the active fibre is preferably isolated from thehemicellulose fraction of cereal grains, though parts of the celluloseand lignin fractions can be co-isolated. In an embodiment, part of theester-bonds between lignin and hemi-cellulose will be broken by analkali treatment and become soluble.

More preferably, the hemicelluloses fraction is more than 45, morepreferably 55 to 90 wt % of the active fibre fraction. Other parts ofthe isolated fibre may be beta-glucans, which may amount to for example0.5 to 10% of the fibre fraction.

The fibre ingredient may further comprise digestible carbohydrates,lipids and protein, but generally in an amount of less than 35 wt % ofthe amount of fibre ingredient as will be used in manufacture of theready to use nutritional product. Preferably the amount of digestiblecarbohydrates in the fibre ingredient is less than 24 wt %. The amountof resistant starch in the fibre ingredient may be up to 20 wt %.

The active fibre fraction, respectively fibre ingredient, as disclosedabove can in a further embodiment be combined with dietetic fibres fromalternative sources like gums, mucilage, fractions from pulses or beans,oil seeds, roots or tubers, or fruit or vegetable leafs or be syntheticoligosaccharides like those based on fructose or galactose. Thecombination of all indigestible carbohydrates in the ready to useproduct makes the total fibre fraction (TFF) in the ready to use (RTU)product. However, in a preferred embodiment the amount of the cerealgrain based fibre fraction will be more than 40 wt %, more preferablymore than 60 wt % of the amount of TFF.

Different fibre fractions in the TFF may be included to improve otheraspects of gut function. In particular this improvement is modulated byalternative mechanisms than ameliorating the activation of theenterochromaffin cells, especially those present in the proximal partsof the small intestine. These mechanisms may include improving colonicfunction, e.g. by increasing bulking of luminal contents, or modulatingfermentation patterns in the colon.

Preferably the TFF includes soluble fibres based on mannans, likeglucomannans, galactomannans, galactoglucomannans or otherheterosaccharides based on a mannose oligomers or mannose polymers.These mannans can be isolated from, for example, guar gum or Konjac gum,by applying methods known in the art. It is preferred to have thesemannans at least partially hydrolysed to arrive at fibre ingredientwherein more than 88 wt % of the oligosaccharides have a degree ofhydrolysis between 2 and 50. Suitable sources are commercially availableand include for guar gum Benefibre and Sunfibre. In a specificembodiment, the amount of mannans in TFF is, more than 10 wt %,preferably 14-40 wt %. Preferably the mannan fraction in the TFForiginates from non-grain fibres.

In an embodiment, the amount of indigestible fibres in the TFF that arepredominantly homo-saccharides, like inulin, fructo-oligosaccharides andgalacto-oligosaccharides remains below 37 wt %, and is preferably lessthan 26 wt % in order to prevent over-activation of enterochromaffincells.

In an embodiment, the total fibre fraction in the RTU product comprises2 to 50, preferably 3 to 40, more preferably 4 to 30 wt % galactans.These galactans are derived and isolated from gums like acacia gum.Preferably these galactans are heterosaccharides comprising at leastmore than 7 wt % non-galactose sugar moieties and more than 88 wt % mayhave a degree of polymerisation of 3 to 80.

In an embodiment, the total fibre fraction in the product compriseslittle or no pectinic substances and/or added acidic oligosaccharides,in order to achieve the ameliorating effect on the enterochromaffincells and prevent the release of too much acetate in the gut. Thoughsome uronic acids will be present in the cereal fibre and naturalfibres, as substituted to xylans or as minor constituents in the rawingredient, the nature of such indigestible saccharides differs fromadded purified pectins as disclosed in WO2010/147472. In particular theamount of added pectins, added pectin hydrolysates and added uronicacids is less than 40, preferably less than 10 wt % of the total fibrefraction in the product. In addition the product according the inventiondiffers from that disclosed in WO 2010/147472, because it comprises in apreferred embodiment no or relatively little D-ribose, in order toprevent undesirable colour modification of the product during heatingand shelf life. The amount of added D-ribose in a product of theinvention is therefore less than 10, more preferably less than 2 wt %,and most preferably it is virtually absent.

The total dietary fibre fraction (or short ‘dietary fibre’) in a productaccording to the invention is usually a combination of different dietaryfibre molecules. The dietary fibre molecules typically are carbohydratesthat are at least substantially composed of a plurality ofmonosaccharide units. The dietary fibre molecules may differ inmolecular weight, in chemical structure (such as difference inmonosaccharide unit's composition, manner in which they are arranged inthe molecule, difference in linkage between the monosaccharide units). Amodified fibre may in particular be an enzymatically modified fibre, inparticular modified with an enzyme that alters the structure ormolecular weight of the fibre components.

The total fibre fraction (TFF) is formed by the total of allindigestible carbohydrates in a product, such as a nutritionalcomposition in accordance to the invention, which may in particular be aready to use (RTU) product. In an embodiment, the total fibre fractionin the (ready to use dietetic or) nutritional product (for use)according the invention consists for more than 95 wt % ofoligosaccharides having a degree of polymerisation of 3 or more.Indigestible or partially digestible disaccharides are therefore notcalculated as fibre. In a preferred embodiment indigestibledisaccharides are not added in the manufacture of the ready to useproduct.

In particular, a dietary fibre is provided that is effective indecreasing the release of serotonin in the gut under physiological andstressed situations. This applies to the release of 5HT afterconsumption of the product compared to prior art products, which intendto improve central serotonergic subsystems. It also applies to othernutritional products that are to be consumed by the patient during thatsame day.

In an embodiment of the invention, the TFF has a prebiotic index below4.2. (as defined by Roberfroid 2007, J Nutrition, 137, 830S-837S). Arelatively low prebiotic index of the cereal fibres of the invention andof the total fibre fraction in the ready to use product reflects thatthe product does not achieve its effect by maximizing its prebioticpotential as suggested by WO2010/147472 for a blend of fibre, includingacidic oligosaccharides and rice bran, baker's yeast and D-ribose toinhibit virus replication and by EP-B 1383514 to decrease inflammatoryprocesses and activate non-specific immune parameters by a blend offructo-oligosaccharides and inulin, and by WO02/060279 which aims toinduce a prebiotic effect by oral administration of alpha-lactalbumin.

In an embodiment of the invention, the fibre may also demonstrate arelatively low prebiotic effect with respect to those bacteria that areadhered to the mucosa of the small intestine.

The mucosa-associated microbial community in the small intestine can bemeasured by applying the ProDigest or LabMET methodologies as are knownin the art (e.g. from WO2011/060123). The adhesion-related prebioticindex may be less than 8.0, preferably less than 7.2, using thecalculation method as disclosed in Van den Abbeele, et al, ApplMicrobiol Biotechnol 2009, in Horremans et al Helicobacter 2012, orequivalent method. The adhesion characteristics of microorganisms can befurther determined in vitro by applying an in vitro gut cell model, forexample the Caco-2 cell based model as disclosed by Grootaert et al JMicrobiol Meth 2011, 86 (1), 33-41 al alternative methods.

In particular, a fibre for use in accordance with the inventiongenerates a type of metabolism in the microorganism present in or nearthe mucosa in the small intestine that the GPR41, as for example isexpressed in the sympathetic ganglia in the nervous system are notstrongly activated, which decreases the signalling through the spinalsympathetic nerves to the CNS. This prevents over-activation of thesympathetic nervous system and diarrhoea.

In particular, the fibre fraction induces the reactions onenteroendocrine (EE) and enterochromaffin cells (EC) cells and on thesympathetic system. The effect of the fibre is observed in both femalesand males and is observed especially in persons having a body mass indexof less than 25 kg/m2 and especially in the male population.

The different pattern of free fatty acids that are released by mucosalbacteria in the small intestine activate differentially the free fattyacid receptors that are present in the gut, like the chemoattractantreceptor GPR43. The low degree of activation of GPR43 after oraladministration of the dietary fibre—when administered to asubject-ensures a proper immune reaction during the intensecommunication between microorganisms, as present in the mucosa of thesmall intestine, and the neighbouring epithelial cells, in particularthe enterochromaffin cells. The communication may include activation ofserotonin receptors but also Toll-like receptors and Nucleotide-bindingoligomerization domain-like receptors, like for example NOD-2, which inone embodiment all maintain an activated state after oral administrationof the fibre fraction. It has to be noted that the nature of luminalbacteria can differ from mucosal bacteria.

After oral consumption of the product the need for a high activity ofT-helper 17 cells is decreased, which increases the balance between theIL-10 producing regulatory T cells and the Th17 cells in the GIT of thechild or adult, though it maintains a sound release of IL-12 bydendritic cells in the gut to maintain a Th1 response, when required,e.g. to combat opportunistic infections by pathogens that may haveentered the gut or developed in the lumen. The new balance betweenimmune cells in the gut, especially in the small intestine, decreasesthe release of interferon-gamma and maintains the concentration oftryptophan in the intestine on a properly high level and keeps theconcentrations of potentially damaging tryptophan catabolites low.

Typically, the active fibre comprises fibre selected from the group ofunmodified or modified cereal fibre, preferably an unmodified ormodified rice fibre.

It is preferred that 10 wt % or more of the total fibre in the productis from cereal origin. Cereals in particular include plants belonging tothe group of rice, wheat, rye, triticale, barley, oats, millet, amaranthand corn. Preferably the fibre in, or attached to or surrounding thegrain is used for a product of the invention.

In a preferred embodiment, the amount of the cereal grain based fibrefraction will be more than 40 wt %, more preferably more than 60 wt %,based on total fibre. This is in particular preferred for an embodimentwherein the fibre is part of a food supplement.

The fibre is preferably isolated from the cereal by treatment of thecereal grains Preferably the fibre is isolated from the caryopsis and/orthe nucellar epidermis, the seed coat and/or pericarb of the cerealgrain. The cereal fibre ingredient in this embodiment according theinvention comprises predominantly fibres derived from pericarp, tegumen,aleurone, scuttelum, epiblast and/or plumule. Preferably, the amount offibres derived from these parts of the grain kernel are more than 85 wt% from the total fibre in the fibre ingredient.

In an advantageous embodiment the TFF comprises cereal fibre (other thanresistant starch, gums, FOS, GOS and polydextrose; typically ‘activefibre’) and at least two, preferably at least three different fibresdifferent from the cereal fibre. Such embodiment is referred to hereinas a ‘multifibre blend’. The multifibre blend may be provided as a foodsupplement or be a part of a food supplement, or be part of anutritional product, further comprising other nutrients, in particularone or more macronutrients, such as digestible carbohydrates, peptides(in particular protein), and lipids (in particular triglyceride), It maybe used for any use according to the invention. In a specificembodiment, a multifibre blend is for use in a medical food and/or bepart of a food for the treatment of malnourishment

The multifibre blend preferably comprises the cereal fibre and at leasttwo, preferably at least three members of the group of 1/ fibres frombeans or pulses, 2/ fibres from leaves, fruit skin, vegetables or fruit,3/ fibres from tubers or roots, 4/ gums. In a particularly preferredembodiment, the multifibre blend comprises the cereal fibre and at leasttwo or at least three members of said groups, different from resistantstarch, the multifibre blend further comprising resistant starch, whichmay be from cereal, beans or pulses, leaves, fruit skin, vegetables orfruit, tubers roots, or from a different source. In a preferredembodiment, the multifibre blend comprises the cereal fibre and at leasttwo, preferably at least three members of the group of 1/ fibres frombeans or pulses, 2/ fibres from leaves, fruit skin, vegetables or fruit,3/ fibres from tubers or roots, 4/ gums from Acacia, guar, Konjac orchia. In a particularly preferred embodiment, the multifibre blendcomprises the cereal fibre and at least two, preferably at least threemembers different from resistant starch of the group of 1/ fibres frombeans or pulses, 2/ fibres from leaves, fruit skin, vegetables or fruit,3/ fibres from tubers or roots, 4/ gums from Acacia, guar, Konjac orchia. In addition, resistant starch may be present from any source, inparticular from a cereal, root or tuber. In a preferred embodiment theTFF of a product in accordance with the invention comprises the cerealfibre and further fibre from at least three of the following groups, 1/gums, 2/ fibres from beans or pulses, 3/ fibres from leaves, fruit skin,vegetables or fruit, 4/ fibres from tubers and roots, 6/ fibres from oilseeds, nuts, polydextrose (e.g. Litesse) or additional oligosaccharidese.g. fructo or galacto-oligosaccharides. In a particularly preferredembodiment, in addition to cereal fibre, at least fibres are presentfrom three of the following groups 1/ gums, 2/ fibres from beans orpulses, 3/ fibres from leaves, fruit skin, vegetables or fruit, 4/fibres from tubers, 5/ resistant starch. Herein, the fibres from theplant sources (cereal, beans, pulses, leaves, fruit skin, vegetables,fruit, tubers roods, oil seeds, nuts) are preferably different from theselected gum, resistant starch, polydextrose or additionaloligosaccharides.

In an advantageous embodiment, the multifibre blend forms part of anutritional product comprising one or more macronutrients selected fromthe group of digestible carbohydrates, lipids and peptides. In aspecifically preferred embodiment, the multifibre blend forms part of anutritionally complete food product.

Suitable sources for cereal fibre are in particular rice, oats, corn,wheat, rye, barley, triticale, amaranth, and millet/quinoa The cerealfibre is preferably selected from rice, wheat and oats. In particular,good results have been achieved with a rice fibre. The weightpercentage, based on total fibres, for cereal fibre in the multifibreblend usually is at least 20 wt. %, based on total fibre, preferably,30-80 wt. %, in particular 30-50 wt. %.

The gums are in particular selected from acacia gum, guar gum or chiagum. Preferably they are partially hydrolyzed saccharides derived fromacacia gum and/or guar gum and/or chia gum. More preferably thishydrolysis is to a degree that more than 60 wt % of the gum fibre has adegree of polymerization of 3 to 20. This is in particular preferred inview of rheological considerations inside the gut, as a high content ofintact gums may give rise to an undesirably high viscosity in the guts,even in the colon. This impairs digestion and increases the degree ofactivation of the sensing cells, when measured over the whole intestine.Preferably the amount of intact natural gum polysaccharides in the blendis therefore less than 20 wt % and more preferably less than 5 wt %,dependant on the nature of the gum. For example gum having a high degreeof polymerization should be less than 5 wt % while gums that aresignificantly hydrolyzed to values of 15 or below, can be included in upto 20 wt % in the blend.

The weight percentage of gums based on total fibre is usually 25 wt. %or less, in particular 2 to 18 wt. %

The tuber or root starch is preferably from a tuber or root selectedfrom the group of onion, chicories, beta vulgaris (beetroot, sugarbeet), potato, more preferably from chicory and beat.

The weight percentage, based on total fibres for fibres from a tuber orroot in the multifibre blend usually is 80 wt. % or less, preferably5-60 wt. %, in particular 10-50 wt. %.

Suitable sources for fibre from pulses or beans are in particular soybeans, pea (e.g. pisu sativum) Azuki beans, Phaseolus varieties (e.g. P.vulgarus) and lupin seeds. Preferred sources are pea and soybeans. Theweight percentage, based on total fibres for fibre from pulses or beansin the multifibre blend usually is 40 wt. % or less, in particular 2-30wt. %.

Preferred sources for fibres from fruits or leaves from plants areplantain (including banana), prune, cabbage, tomato, squash, sugarcane,bagasse and citrus fruit. Particularly preferred is fibre from plantain,in particular banana. The weight percentage, based on total fibres forfibres from vegetable leaves or fruits in the multifibre blend usuallyis 40 wt. % or less, in particular 1-30 wt. %, more in particular 2-20wt.

Suitable sources for resistant starch include cereals, for instancecorn, wheat, rice, and tapioca. The fibre ingredients as derived fromdifferent origins can comprise some resistant starch (RS). In thecontext of this patent application we define the resistant starchingredient as being an ingredient which comprises at least 80 wt %resistant starch per 100 g dry resistant starch ingredient. Whenresistant starch is used as such the sum of resistant starch from allfibre ingredients is meant, including the RS from the RS ingredient. Anexample of a RS ingredient is Novelose 300 The resistant starch ispreferably resistant starch from rice. The weight percentage, based ontotal fibres, for resistant starch in the multifibre brend usually is 40wt. % or less, in particular 3-35 wt. %. In particular, the resistantstarch is present in a particulate form, such as resistant starchescomprising more 80 wt % particles having a size of 2-15 micron.

Suitable fibres from oil seed include in particular, fibres from sunflower seeds and fibres from flax seeds. The weight percentage, based ontotal fibres for fibres from oil seeds, polydextrose (e.g. Litesse),oligosaccharides e.g. fructo or galacto-oligosaccharides in themultifibre blend usually is 40 wt. % or less, in particular 3-15 wt. %.

The total content of in the multifibre blend is usually . . . or less,in particular . . . or less.

Commercial preparations are currently available and include

Sugar beet fiber from Nippon Beet Sugar being about ⅓ rd soluble

Apple fiber (about ⅓rd soluble)

Chicory: raftiline

Soy fibre e.g. Fibrim

Resistant starch (Novelose)

Oat bran (about ½ soluble; Vitacel)

Commercial sources of oligosaccharide and resistant starch and RS andtheir way of analysis have been disclosed in US2010/0317573, which ishereby incorporated as a reference

Optionally the multifibre blend comprises hydrolyzed fibres(fructo-oligosaccharides, galacto-oligosaccharides)

The multifibre blend comprises active fibre according the invention, andtypically additional fibres that are part of a normal diet. This is 1/to change as little as possible for the consumer/patient which wouldconsume a healthy mixed fibre pattern and 2/ induce a gradual andmaximal fermentation of the blend and induce a healthy gut flora, whichwould a/generate an amount of gas per time unit which can be coped withby the individual, b/ synthesize vitamins, c/ facilitate absorption ofnutrients and medication, d/ interact in a symbiotic way with the host,e/ decrease the amount of ammonia and sulphides that are generated inthe colon. Such healthy gut microbiota may comprise increased amounts ofRoseburia and eubacteria. In one embodiment this encompasses eubacteriumlimosum.

In a preferred embodiment, the active fibre comprises a xylan. The xylanpreferably consists for more than 40 wt % of xylan-moieties, theremainder being one or more of arabinose- or glucuronic acid, or4-methylated glucuronic acid or other monosaccharide moieties. These mayoriginate from cereals. They can be linear or branched. In the preferredembodiment the xylans are at least branched for more than 10%, morepreferably 13-60, most preferably 15-40 wt %. The branched xylanscomprise more ferulic acid than linear xylans and in addition thechanged structure of the xylans are thought to have different effects ondiet-induced serotonin release in the gut, e.g. through a different bileacid mediated effect on the small intestine. This is especiallyrelevant, if the medical food or medication, taken by a subject treatedwith a dietary fibre in accordance with the invention, raises tryptophanconcentrations in the gut tissue.

In a preferred embodiment, the active fibre constituent, comprisingxylan, or part thereof, is isolated by applying a treatment at alkalinepH or an extraction at such high pH. This treatment at alkaline pH mayserve to solubilise digestible carbohydrates from the matrix tofacilitate their removal in the preparation of the fibre isolate, butalso allows breaking of the ester bond between hemicelluloses andlignin, as they occur in the raw grains. For the latter it is useful toadd a reducing agent like sodium borohydride. This allows manufacture ofa fibre ingredient which is relatively low in lignin and cellulose,relatively high in ferulic acid

In particular, the fibres isolated from the cereal may be enriched inhemicellulose, compared to the total fibres content of the cereal fromwhich the fibre originates. More in particular, the fibre fraction maybe enriched in arabinoxylans.

Thus, the active fibre preferably comprises hemicellulose. Thehemicellulose is preferably isolated from the hemicellulose fraction ofcereal grains, though parts of the cellulose and lignin fractions can beco-isolated. More preferably, the hemicelluloses content is more than45, more preferably 55 to 90 wt % of the fibre fraction.

Preferably, the active fibre comprises fibre, isolated from thehemicellulose fraction of cereal grains, though parts of the celluloseand lignin fractions can be co-isolated.

In particular, the dietary fibre may be composed for at least 11 wt. %of xylans, preferably about 13 to about 80 wt % of the fibre fraction.

Preferably the xylans are heterosaccharides. As used herein, the termleterosaccharides' is used for at least two different monosaccharideunits. It is in particular preferred that more than 4 wt % of the xylanconsists of saccharides other than xylose.

These heteroxylans in particular include arabinoxylans (AX). In apreferred embodiment, the active fibre comprises an arabinoxylan,present in an effective amount for use in the prophylactic ortherapeutic treatment in accordance with the invention.

In a specifically preferred embodiment, the arabinoxylans are branched,which ensures the formation of non-linear molecules. The arabinosesubstituents may make up from 0.05 to about 1 times the amount of xylosein the xylan. Part of the xylans may be (arabino)glucuronoxylans (AGX),glucuronoxylans or (glucurono)arabinoxylans (GAX), using the terminologyof Ebringerova, et al, in Adv Polym Sci, 2005, 186, 1-67. The sum of AGXand GAX may be 0.4-30 times the amount of pure arabinoxylans. In aspecific embodiment the amount of AGX is 0.5 to 24 times the amount AX.

In addition, or alternatively the xylan may comprise one or moremonosaccharide units other than arabinose linked to xylose. Inparticular such unit may be selected from the group of uronic acidunits, methylated uronic acid units, fucose units and galactose units.

One or more of the monosaccharide units in the xylan may be substitutedwith a phenolic compound, for instance like ferulic acid. In a preferredembodiment, the amount of ferulic acid in the fibre ingredient is 0.1 toabout 6 wt. %. After (oral) administration of the product, a major partof the ferulic acid will in particular be released in the intestine,more in particular in proximal parts of the small intestine, by theaction of intestinal enzymes, e.g. those originating frommicroorganisms.

In a specific embodiment, the xylans are partially hydrolysed prior toinclusion in the product in order to improve solubility in the ready touse product or to improve the ameliorating effect on lumical sensingcells, i.e. enterochromaffin cells and the effect of the product. Inparticular, a suitable degree of hydrolysis (DH) is 2 to 10. This can beachieved by applying an alkali treatment, an enzymatic hydrolysis or afermentation process.

In particular, in the manufacture of the fibre ingredient one or moreenzymatic hydrolysis steps can be applied to remove starchy material,e.g. with amylase or mixtures of enzymes that have glycolytic activity,or to break down the matrix to allow release of its constituents in theslurry of ingredient (like pullulanases, e.g. those isolated frombacteria as known in the art, cellulases or hemicellulases).

Further, an enzymatic treatment may involve the hydrolysis of polymericfibre molecules into oligosaccharides. Examples of suitable enzymesinclude the xylanases (e.g. endoxylanases, e.g. derived from bacillussubtilis.

In a preferred embodiment the enzymatic process includes a hydrolysis bya xylanase. Suitable sources of xylanase which are capable ofhydrolysing cereal xylans are known in the art. In a preferredembodiment the fermentation step includes a step wherein the cerealfibre material is subjected to fermentation by a lactobacillus or acombination of a lactobacillus with yeast and optionally

In a preferred embodiment the active fibre comprises arabino-xylans thathave an average degree of polymerization that is at least 10% lower thanin the natural grain, either by the application of the isolation processor by the enzymatic step. More preferably arabinoxylans which have adegree of polymerization between 3 to 18 make up more than 60 wt % ofthe arabinoxylans in the fibre ingredient. This facilitates itsfunctionality in the small intestine.

The TFF may comprise a beta-glucan, which may in particular amount to0.5 to 10 wt. % of the fibre fraction. The fibre does not need to beprovided in a product according to the invention as a chemically pureingredient. For example, the ingredient used for providing fibre in aproduct of the invention (the fibre ingredient), may still compriseother components than the fibre, that originate from the source fromwhich the fibre ingredient is obtained, such as the germ or (minoramounts of) parts of the hull of a cereal from which the fibreingredient is obtained. In particular, the ingredient used for providingfibre in a product of the invention may further comprise digestiblecarbohydrates, lipids and protein, but generally in an amount of lessthan 35 wt % of the fibre that is used in the nutritional product.Preferably the amount of digestible carbohydrates in the fibreingredient is less than 24 wt %. The amount of resistant starch in thefibre ingredient may be up to 20 wt %. In a further embodiment, thefibre comprises a dietary fibre selected from the group of gums,mucilage fibres, fractions from pulses, oil seeds, roots, fruits, leafs,such as vegetable leafs, and synthetic oligosaccharides. Said fibres maybe an additional source of active fibre (e.g. hemicelluloses, xylans orarabinoxylans from such a source) but may also provide another kind offibre molecules, which may have a different purpose than the activefibre.

Synthetic oligosaccharides may in particular those comprising fructoseunits or galactose units. A fibre from any of said sources is preferablyused with an active fibre selected from the cereal fibres,hemicelluloses, xylans and arabinoxylan, such as described herein.

One or more of these fibres in the TFF may be included to improve one ormore aspects of gut function. In particular such improvement ismodulated by alternative mechanisms than ameliorating the activation ofthe enterochromaffin cells, especially those present in the proximalparts of the small intestine. These mechanisms may include improvingcolonic function, e.g. by increasing bulking of luminal contents, ormodulating fermentation patterns in the colon.

The fibre fraction usually comprises soluble fibre. Insoluble fibre mayalso be present.

In a preferred embodiment, at least 40 wt %, more preferably more than60 wt % of the dietary fibre is soluble in water at 20 degrees Celsius.

The soluble fibre fraction preferably includes a beta-glucan orgalactomannans originating from hydrolyzed or partially hydrolyzed guargum. Preferably the soluble fraction comprises 15 wt % or more fibresselected from the group of beta-glucans, more preferably 18-90 wt %.This is thought to induce a total fermentation pattern that improves gutperformance in treatment protocols meant to promote serotonin signallingin the brain.

Beta 1,3-glucans form a group of non-digestible carbohydrates which canbe found in several types of ingredients. For example yeast, mushrooms,algae and several types of cereal fibres comprise them. The beta-(1,3)glucans can comprise linear chains of monosaccharides which arepredominantly connected to each other by a Beta 1-3 bond, and optionallypartially by beta 1,6-, as occur in some yeasts, and/or optionally bybeta 1,4 linkages, as occur in cereals or grains. The glucans can belinear or be substituted with for example other saccharides, withpeptides or amino acids, and/or with lipids or fatty acids and can besoluble or insoluble in natural conditions. They can have a wide rangeof molecular weight and occur in several special forms, which eachdemonstrate different properties and biological activities. Of specialinterest are beta 1,3 glucans which are partially substituted withsaccharides which are linked by a beta 1,4 linkage to the beta 1,3 chainas occur in cereal and grain fibre. In nature they typically occur to ahigh extent as insoluble globules which can be recognized undermicroscopy as particles which can have a diameter of 10 micrometer.Disruption of these globules is useful to make them soluble and toincrease biological efficacy. Sonification and high shear or highpressure homogenization are suitable techniques to achieve this. Thebeta1,3 glucan molecules can absorb several times their molar amounts ofwater and commercial dry preparations demonstrate different degrees ofdehydration.

The total dietary fibre in the product preferably comprises insolublefibre. Such fibre induces a specific fermentation pattern, due to thedifferent types of bacteria that preferentially will start to grow. Inparticular, it may contribute to a favourable production of metabolitesother than acetate in the colon.

If present, the insoluble fibre content, based on total fibres in theproduct, preferably is at least 8 wt %, more preferably 18 to 72 wt. %,in particular 22 to 58 wt %. Such high insoluble fibre contents areusually provided in a semi-solid—or solid product. The amount ofinsoluble fibre in the product can be selected to be higher if a moresolid matrix is selected as vehicle for the active components to beadministered.

In a specific embodiment, the insoluble fibres comprise resistantstarch. In a preferred embodiment, the resistant starch is retrogradedor RS3 starch. In a further preferred embodiment, the resistant starchfraction comprises more than 50 wt % linear polymers of alpha 1,4glucans which have a degree of polymerization between 10 and 35.Suitable sources of such resistant starches are beans, peas,heat-treated potatoes and heat-treated cereals. Simultaneous presence inthe colon of resistant starch and beta glucans, in combination with thexylans will support of growth of the right type of butyrate generatingbacteria species. A preferred content of resistant starch in the fibrefraction is 3 wt % or more, more preferably 5-60 wt %, based on totalfibre. Resistant starch is defined to be as those starches which remainintact after digestion during 2 hours in the system of Englyst et al AmJ Clin Nutr 1999, 69, 448-454.

Preferably the TFF includes one or more soluble fibres based on mannans,like glucomannans, galactomannans, galactoglucomannans or otherheterosaccharides based on a mannose oligomers or mannose polymers.These mannans can be isolated from for example guar gum or Konjac gum,by applying a specific combination of methods known in the art. It ispreferred to have these mannans at least partially hydrolysed, wherebythe mannan ingredient consists for more than 88 wt % of oligosaccharideshaving a degree of hydrolysis between 2 and 50.

Suitable sources for the mannans are commercially available and includefor guar gum Benefibre and Sunfibre. The amount of mannans in TFF is inone embodiment more than 10 wt %, preferably 14-40 wt %.

In a specific embodiment, the amount of indigestible homo-saccharides,i.e. saccharides formed of a single type of monosaccharide units, likeinulin, fructo-oligosaccharides and galacto-oligosaccharides is below 37wt %. The content of indigestible homo-saccharides is preferably lessthan 26 wt %, in order to prevent overactivation of enterochromaffincells.

In a specific embodiment the total fibre fraction in a (RTU) product(for use) according to the invention comprises 2 to 50, preferably 3 to40, more preferably 4 to 30 wt % galactans. These galactans are usuallyderived and isolated from gums like acacia gum. Preferably thesegalactans are heterosaccharides comprising at least 7 wt % non-galactosesugar moieties. Preferably more than 88 wt % has a degree ofpolymerisation of 3 to 80.

In a specific embodiment the total fibre fraction in the product (foruse) according to the invention comprises little or no pectinicsubstances and/or added acidic oligosaccharides, in order to achieve theeffect on the enterochromaffin cells and behaviour as disclosed in thispatent application and prevent the release of too much acetate in thegut. Though some uronic acids will usually be present in cereal fibreand other natural fibres, as substituted to xylans or as minorconstituents in the raw ingredient, the nature of such indigestiblesaccharides generally differs from added purified pectins as disclosedin WO2010147472. In particular the amount of added pectins, added pectinhydrolysates and added uronic acids is less than 40 wt. %, preferablyless than 10 wt % of the total fibre fraction in the product (for use)in accordance with the invention.

In addition the product (for use) according the invention comprises in apreferred embodiment no or relatively little D-ribose, in order toprevent undesirable decolourisation of the product during heating andshelf-life. The amount of added D-ribose is therefore preferably lessthan 10 wt. %, more preferably less than 2 wt %, and most preferably theproduct is essentially free of D-ribose.

The fibre may have a relatively low content of acetogenic fibres, or befree of acetogenic fibres, like inulin and fructo-oligosaccharides andof pectins or acidic homosaccharides which comprise less than 10%saccharides other than a uronic acid. The content of acetogenic fibres,if present, in the fibre fraction is usually less than 85 wt %,preferably less than 40 wt %, more preferably less than 10 wt % or thefibre fraction. This not only ensures a proper release of short chainfatty acids other than acetate, but also decreases the release of gasesfrom the fermentation in the gut. This therefore also improvesgastrointestinal comfort and decreases abdominal bloating, andflatulence. The inclusion of the claimed fibres from cereal origin, andthe presence of the specific beta glucans, resistant starch and thespecific xylans, also in combination with the mannans as mentionedearlier, ensure this release of fatty acids while decreasing the amountof gas released in the gut during fermentation. The fermentation gasesinclude hydrogen, methane, nitrogen and other gases. In an advantageousembodiment, administration of the fibres according the invention preventalso a decrease of faecal pH below a value of 7.0, preferably below 7.1,and induces a stool pH most preferably between 7.15 to 7.5, as measuredby determining acidity in the stool. This reflects the presence of anon-acetogenic microflora in the colon as a result of consuming theproduct.

In particular, the dietary fibre, combination or nutritional compositionfor use according to the invention, wherein under conditions existing inthe colon of a subject to which the fibre (in the combination, in thenutritional composition or in another form) is administered, at leastpart of the fibre is fermented thereby forming propionate, butyrate oracetate, wherein the ratio of the molar amounts of the sum of the amountof formed propionate plus butyrate to the amount of formed acetate is atleast 0.2 and preferably in the range 0.25 to 0.61, most preferably inthe range of 0.56 to 0.61. Such fermentation pattern may be induced by amodification of the gut flora by the diet, for example by a change inthe ratio of the amounts of the phylum Firmicutes to Bacteroidetes to aratio of more than 1.5.

The cereal fibre ingredient preferably impart a relatively a lowviscosity, when dispersed or dissolved. This allows a high palatabilityof the product and thus compliance. Preferably, the fibre will not causea significant increase of viscosity of the luminal contents. Inaddition, the low viscosity allows rapid digestion of the foodcomponents and their rapid absorption. The low viscosity does not impaira proper neuro-endocrine response due to free interaction of luminalcontents with the gut epithelium.

The examples in this document disclose several of the fibre blends thatcan have the ameliorating effect on the neuro-endocrine response ascaused by oral intake of a medicine or nutritional product.

The content of dietary fibre in a nutritional composition of theinvention is usually at least 2 g per 100 g of the total nutritionalcomposition, in particular at least 5 g per 100 gram, more in particularat least 6 g per 100 g. The content, in particular in a ready-to-eatproduct, is usually less than 50 g per 100 g, in particular 40 g per 100g or less.

Usually, the total content of hemicellulose, including xylans (includingheteroxylans, such as arabinoxylans) is at least 0.5 g per 100 g of thetotal nutritional composition, in particular at least 2.5 g per 100gram, more in particular at least 5 g per 100 g. The total content ofthese fibres, in particular in a ready-to-eat product, is usually lessthan 50 g per 100 g, in particular 45 g per 100 g or less, more inparticular, 35 per 100 g or less.

For a liquid product, the fibre content is preferably in the range of2-15 g/100 g of the composition. For a semi-solid product, the fibrecontent is preferably in the range of 6-24 g/100 g of the composition.For a solid product, the fibre content is preferably in the range of6-40 g/100 g of the composition

Per day about 20 to about 1000 g of the product should preferably beconsumed to induce the effect as desired. Typically the dose per daywill be about 30 to about 400 g. This dose will typically be packaged in1 to 10 portions to allow manufacture of ready to use package units. Oneembodiment is a liquid packed in a container of 30 to 125 ml volume.

The Protein Fraction

The protein fraction is defined to be the amount of nitrogen in theproduct, as determined by applying the Kjeldahl method of analyses,multiplied by 6.25. The protein fraction comprises compounds thatcomprise more than 66 wt % amino acid units in the molecule. Thus, itincludes, free amino acids and its salts, esters of amino acids, andpeptides, including intact and hydrolyzed proteins. The protein can besubstituted with a lipid, carbohydrate or other components The non-aminoacid part of the protein fraction can be nitrates and other nitrogeneousproducts.

When referred herein to amino acids, generally the proteinogenic aminoacids are meant. Thus, when referring to doses of amino acids, the dosefor the L-isomer is meant, except for glycine. Though the human body hasa capacity to convert D-isomers to L-isomers, and racemic mixtures ofamino acids could in some cases be useful in the context of theinvention, the use of the L-isomers in the absence of D-isomers ispreferred.

Advantageously, the protein fraction comprises a peptide having at least7 amino acid units. Though this may induce an allergic reaction inpersons suffering from an allergy for an epitope present in the proteinfraction, the inclusion of such peptide is preferred, in order todecrease the need for inclusion of free amino acids and obtain a morepalatable product. This allows full compliance of the product accordingthe invention by the envisaged subjects to be treated with a productaccording to the invention.

The protein fraction in a medical nutrition or nutritional product cancontribute to the sating or nausea-inducing properties of the nutritionor the product. Several ways of action have been identified in the art.Some proteins can release peptides after digestion in the gut whichinduces the release of a high amount of CCK or other neuropeptides whichare known to cause nausea and satiety. Other proteins may clot in thestomach when exposed to high acidity and thus activatepressure-sensitive cells which are located in the stomach and whenactivated cause satiety. A third mechanism may be the activation ofsensing cells in the proximal part of the small intestine whilesupporting serotonin biosynthesis by providing a relatively high amountof its precursor tryptophan. Though obviously a nutritional product canbe designed to have a protein fraction that induces the lowest feelingsof nausea and satiety, the benefits of the cereal fiber become evidentwhen the medical food would comprise such satiety-inducing proteins.

The satiety-inducing properties of a protein become most evident whenthe protein is present in high concentrations. So in a preferredembodiment the fibre is present in a medical food or nutritional productwherein the protein content is more than 8 g per 100 ml. In a differentembodiment the protein fraction in the product would contribute morethan 18% of the energy of the product, using the Atwater values for theamount of energy that is generated by lipids, proteins and digestiblecarbohydrates and a value nil (zero) for non-digestible carbohydrates.

A tryptophan source is usually provided in combination with the (active)dietary fibre in a use according to the invention. Tryptophan may beadministered separately or together with the dietary fibre.

In an embodiment, the tryptophan source comprises free tryptophan, asalt thereof, an ester thereof, or compound having an amide or peptidebond to tryptophan, e.g. a dipeptide comprising a tryptophan unit.

The tryptophan content (including tryptophan present in bound form inpeptides and other compounds comprising a tryptophan unit, such as antryptophan ester) in a nutritional composition of the invention isgenerally 2 mg/g of the total composition or more, preferably 3 mg/g ofthe total composition or more. Usually the content is 6 mg/g or less, atleast in liquid products. The content may be higher though, inparticular in case the composition is a concentrate-product that is tobe diluted before administration, e.g. reconstituted in water or blendedwith another nutritional product.

In an embodiment, the ratio of the weight of tryptophan to that of thelarge neutral amino acids leucine, isoleucine and valine in the proteinfraction of the product is at least 0.22, preferably 0.23 to 20 and mostpreferably 0.28 to 4 Preferably the ratio of the weight of the sum ofleucine plus isoleucine and valine to the weight of the sum ofthreonine, histidine and lysine is smaller than 2.8 preferably 0.8 to2.4.

Advantageously, in a use of the invention, the dietary fibre andtryptophan are administered together as part of a nutritionalcomposition. To this purpose, cereal fibre; rice fibre or a fibresimilar thereto are in particularly advantageous.

The use of the dietary fibre, such as cereal fibre, which may be ricefibre, in combination with tryptophan is advantageous for an amplesupply of rapidly available tryptophan to the blood compartment afteroral intake and a low supply of other amino acids, which hinder passageof tryptophan over the blood brain barrier. So the amino acids in thedietetic product have a relatively high weight ratio of tryptophan tothe sum of large amino acids, in particular to the large neutral aminoacids (LNAA), i.e. the branched chain amino acids (leucine, isoleucineand valine), tyrosine and phenylalanine.

In particular for a nutritional composition for use according to theinvention it is desirable that it is rapidly digestible. This ensures arelatively low exposure of the lower parts of the GIT to severalcomponents in the food and to dietetic tryptophan, compared toadministering tryptophan in the form of slowly-digestible proteins.

In order to achieve this preferably (1) a protein fraction is used whichcomprises a high weight ratio of tryptophan to the sum of large neutralamino acids and/or (2) the product must allow easy digestion of theprotein fraction. A high ratio is in particular a higher ratio than in aprotein like casein. Suitable proteins include proteins isolated fromwhey, from plants (beans, seed, grains tubers, etc.), from fish, krill,animals (meat, skin, organs), algae, eggs and from mushrooms. Methodsare known in the art to isolate protein fractions from these sources andinclude grinding and milling, sieving, dissolving and solubilising,extraction, separation and purification. Partial hydrolysis may improvetechnological properties of these ingredients.

Especially preferred are protein blends which comprise one or preferablytwo, more preferably three members of the group of pea protein, soyprotein, fish protein, egg protein and whey protein.

In a preferred embodiment the proteins are present in their naturalstate in the product that is ready for consumption. Typically duringmanufacture of the protein ingredients, as well as during themanufacture of blended products which include these protein ingredients,the proteins therein are at least partially oxidized. This inducesintramolecular—and intermolecular disulfide formation, which increasesthe globular character of proteins and hinders access or activity ofdigestive proteases like pepsin, trypsin and chymotrypsin. Therefore ina preferred embodiment, the in the protein fraction in a composition(for use) according the invention natural sulfhydryl bonds are stillpresent for at least 20%, preferably at least 35%, most preferably atleast 80%. This can be measured by measuring the amount of protein boundsulfhydryl moieties and comparing the value with the measured value ofthe protein ingredients as used in the manufacture of the product andobligatory declared on the label of the same product.

The way that the proteins can be protected during manufacture of theingredients or the ready to use product which comprises these proteiningredients are preferably selected from the group of 1/ preventingcontact to oxygen by decreasing the time and extent to which theseproteins can come into contact with atmospheric oxygen, 2/ preventinginclusion of oxidizing substances, 3/ decreasing the rate of reactionwith oxidizing compounds, by optimizing heat treatment and avoidance ofincluding catalyzing substances, like trace elements and redox activesubstances like anti-oxidants, and optionally 4/ applying a separatereducing step when needed.

A relatively low degree of heating, of the product, and in particular ofthe protein fraction avoids denaturation of the protein. The presence ofnon-denatured protein in the product is contemplated to be beneficial inthe nutritional management or other treatment of individuals sufferingfrom negative emotions or introvert behaviour. Non-denatured proteinsand peptides may demonstrate a better digestibility in the proximalparts of the intestine and thus improve uptake of tryptophan in thebrain.

Thus, the inventors believe that during preparation or furtherprocessing of a composition comprising protein, it is advisable thatattention is paid to prevent denaturation of protein. This can be doneby applying an optimization of processing conditions, preventingexcessive heating and the like. The degree of heat treatment which isapplied to the product can for example be assessed by measuring Maillardcomponents and the degree of browning. For the latter reason also theinclusion of reducing sugars, like ribose or fructose, especially intheir monosaccharide form is preferably avoided.

Amino acid composition of the protein ingredients can be measured byapplying methods known in the art, which include acid or alkalihydrolysis of peptide bonds in the protein, purification of the extract,chemical derivatization of the amino acids, chromatographic separationand detection of the individual components.

Preferably a protein is present that induces a postprandial responsewhich includes neurological and endocrine effects in the gut and theenteric nervous system, which modulate satiety, nausea. In addition itis preferred that the proteins will modulate the response of e.g. thepancreas to the systemic concentrations of glucose and amino acids. Thisinduces e.g. a specific pattern of release of insulin and glucagon.These proteins are characterized by inducing a relatively high amount ofglucagon compared to insulin, when compared to conventional proteinblends which are used in casein-based medical food products.

The amino acid composition is preferably optimized to help such effects,in particular the effect on the response on the serotonergic systems. Arelatively high amount of tryptophan to the sum of large neutral aminoacids as been discussed above is therefore preferred.

In addition, it is preferred that the content of the sum of glutamateplus glutamine is preferably high in the protein fraction, in particularmore than 18 g per 100 g protein fraction, more preferably 20 to 26 gper 100 g protein fraction, because this facilitates the functioning ofthe nervous systems in the gastrointestinal tract, in particular theserotonin—activated nervus vagus activity. In a specific embodimentglutamate or glutamine is present in a product of the invention,preferably in the range of 0.4 to 10 g per 100 g of the proteinfraction.

The amount of cysteine equivalents is usually more than 1.7, preferably1.8 to 2.8 g per 100 g of the protein fraction. This allows sufficientrelease of hydrogen sulphide to modulate GIT response in case theproduct would be used in situations for persons who experience apartially inflamed gut. Suitable cysteine equivalents are cysteine,N-acylated forms of cysteine, like N-acetylcysteine and cysteine-richpeptides, like peptides from keratin or other cysteine-rich proteins, orspecific proteins from egg or whey.

The amount of branched chain amino acids is preferably low to get thehighest possible ratio of tryptophan to large neutral amino acids. Sopreferably a composition (for use) according to the invention isessentially free of added free leucine, including a salt thereof.

Preferably a composition (for use) according to the invention isessentially free of added free proline, including a salt thereof.

The amount of threonine in the protein fraction is preferably relativelyhigh in order to allow a proper neuro-endocrine response in malnourishedor elderly patients. Without wanting to be bound on theory the effect ofthreonine is thought to be related to its ability to facilitate properinteraction between luminal contents and enterochromaffin and endocrinecells, either directly or through the mucosal micro-organisms. For thisreason the amount of threonine in the product is preferably more than5.2 and preferably more than 6.2 g per 100 g protein.

This can be achieved by inclusion of a proper protein source, like wheyprotein, or add free threonine or its salts or peptides duringmanufacture, or apply the combination of these measures.

The concentration of arginine in the product is preferably relativelyhigh in order to facilitate the nitric oxide mediated activation of thenervus vagus. Preferably the amount of arginine in the protein fractionis more than 5, more preferably 5.4 to 9, most preferably 5.6 to 8 garginine per 100 g of the protein fraction.

Proteins of plant origin, e.g. from cereals, like rye and wheat have alow weight ratio of tryptophan to the sum of large neutral amino acids.This means that the other proteins in the protein fraction of theproduct must comprise much tryptophan, or alternatively or additionallyone or more other tryptophan sources should be used, such as freetryptophan (as acid, salt) or tryptophan-rich peptides. Preferably addedfree L-tryptophan as amino acid, its salt, its ester, or as anoligopeptide (i.e. a peptide having up to 10 amino acid units), inparticular as dipeptide, preferably is provided in an amount of 0-12,more preferably 0.2 to 4 g L-tryptophan per 100 g of the proteinfraction.

A product of the invention is usually essentially free of casein. Ifpresent, the casein content is typically less than 15 wt. %, preferablyless than 2 wt % of the protein fraction.

The sum of dairy whey proteins and vegetable proteins is usually 5 to100 wt %, preferably 22 to 98 wt % of the protein fraction.

In a specific embodiment, the ratio of the weight of vegetable protein(which is typically low in branched chain amino acids) compared to thatof dairy protein, is at least 0.05 (wt/wt), preferably at least 0.2(wt/wt).

A preferred protein fraction, in particular for use in a treatment of aperson suffering from a mood—or behavioural disorder that is sensitiveto food allergens meets the following features:

tryptophan is more than 1.9 g per 100 g of the protein fraction

the protein fraction comprises free L-tryptophan as amino acid, itssalt, its ester, or as a peptide having 2-6 amino acid residues.

5-95 wt %, based on the total protein fraction, of peptides have 2-6amino acid units.

The dosage of protein is preferably relatively low, in particular lessthan 6 g per dose, preferably less than 5.5 g per dose, more preferablyless than 4.9 g per dose. However, based on the contribution to thetotal energy the protein content in the (ready to use product) ispreferably more than 18 en %, using the Atwater constants for thecalculation. The latter is because other energy-providing components, inparticular lipids,—if present—are preferably in a relatively low amountof in the product. Preferably the product has the form of a liquid orsemi solid.

In a specific embodiment, the protein fraction comprises lysozyme astryptophan source. The amount of lysozyme hydrolysate having a DH ofless than 10, in this embodiment is usually less than 25 wt. %,preferably less than 20 wt %, more preferably less than 10 wt %, of theamount of lysozyme hydrolysate in the product which has a DH of morethan 20. Preferably the amount of tryptophan polypeptides fromhydrolyzed intact protein in the protein fraction is less than 1 wt %.Preferably the protein fraction comprises 80 wt % or less, and morepreferably less than 30 wt % of hydrolysed protein, due to tastereasons.

In an advantageous embodiment, the protein fraction also contributes tothe supporting role of the product as claimed on the functioning of thedopaminergic system. This system includes the release of dopamine whenfood is observed or briefly before it has to be consumed and can bemeasured as an increased appetite. In addition the supporting rolecomprises a better functioning of dopamine receptors, in particular theincrease of the effect of dopamine which is released before or duringthe first stages of eating.

The protein fraction is preferably rapidly digestible, which preventsthat EC cells that are located in the distal parts of the ileum releaseserotonin to a larger extent than the blood platelets can absorb andthus induce a satiating and nausea effect by activating 5HT3 receptorsin the CTZ (chemoreceptor trigger zone) of the medulla.

The protein fraction preferably also induces a relative low CCK releaseby the 1-cells in the duodenum after consumption, because it generallycomprises a low amount of kappa casein. The whey proteins, if present,therefore preferably comprise acid whey. More preferably acid whey ismore than 40, most preferably 51-100 wt % of the whey proteins.

If the nutritional product is in a liquid form, the product preferablyis a homogeneous emulsion comprising at least a protein fraction, lipidscarbohydrates, a fibre and a mineral fraction. After consumption andpassage of the stomach the emulsion as such induces a release ofcholecystokinin (CCK) which is relatively low, compared to prior artproducts.

The product preferably has a relatively low amount of organic acids oris essentially free thereof. In a particular preferred embodiment theamount of organic acids which are typically declared as digestiblecarbohydrates on the label of the product is less than 5 wt %,preferably less than 2 wt % and more preferred less than 1 wt % of thedigestible carbohydrate fraction. When expressed as ratio to theprotein, the amount of organic acids to the total amount of protein inthe product is usually less than 8 g organic acid per g pure protein inthe product, and preferably less than 6 g, more preferably less than 5 gorganic acid per g protein. This criterion applies to organic acids likemono- or di- or tri-carboxylic acids, and in particular to di- andtricarboxylic acids. Most in particular it applies to citrate and itssalts.

This facilitates proteolysis of dietetic proteins of the product alreadyin the stomach, predominantly by allowing rapid acidification of thegastric contents to the pH value which is closer to the optimum valuefor the proteolytic enzymes in the gut, including pepsin. This rapidpre-digestion also allows more rapid passage through the stomach pylorusand allows a more rapid neutralization of the digests that enter theduodenum. This decreases the release of CCK compared to conventionalfoods.

These effects on dopaminergic and serotonergic systems contribute to adesired eating behaviour in individuals in need of the product asclaimed, because the full desired amounts of the product according theinvention are consumed; in other words the compliance to the feedingprotocol with the product as claimed is excellent, preferably more than90%. Compliance with a desired level of intake of healthy nutrients is amajor problem in the individuals suffering from the serotonergicdisorders, depression, behavioural disorders and other diseases asmentioned in this document.

A superior digestion rate of a preferred composition of the invention,including the protein fraction can be accomplished in various ways. Itis therefore preferred to create a low buffer strength or capacity inthe ready to consume product, for a superior digestion rate.

WO2012/092082 discloses low calorie infant formula which allow gooddigestion of dietetic proteins. By decreasing the energy density to avalue of 200-500 kcal/l and by decreasing the amount of microingredientsthat are included to 30-80% of the amounts in normal infant formulapatentee aims to reduce buffer capacity. In the present application theinventors aim to improve digestibility in different ways. The selectionof the nature of the protein has been discussed above. In addition itappears that the matrix of the product is important, for example interms of dry matter content and presence of insoluble material. In thepresent invention a preferred measure to reduce buffer capacity orstrength is to decrease the inclusion of an organic acid in acomposition of the invention. The phosphorous content in the ready toeat product is therefore preferably less than 14 mg, more preferably3-13 mg per g protein fraction in the product. The pH of the product isin the range 3.0 to 7.4 and the osmolarity and viscosity is relativelylow. The content of the protein fraction in a nutritional composition ofthe invention is usually at least 5 g per 100 g of the total nutritionalcomposition, in particular at least 8 g per 100 gram, more in particularat least 14 g per 100 g. The content, in particular in a ready-to-eatproduct, is usually less than 50 g per 100 g, in particular 40 g per 100g or less, more in particular 25 g per 100 g or less.

For a liquid product, the protein fraction content is preferably in therange of 5-9 g/100 g of the composition. For a semi-solid product theprotein fraction content is preferably in the range of 8-20 g/100 g ofthe composition. For a solid product the protein fraction content ispreferably in the range of 14-40 g/100 g of the composition.

The Digestible Carbohydrates

If present, the fraction of digestible carbohydrates preferably has alow glycaemic index (GI). This ensures a small and slow increase of NADHin the cells of the gut, the nervous systems, immune cells and theliver. This is considered to be beneficial for maintaining proper redoxpotential in the cell, while at the same time generating a sufficientlylarge flux of reducing equivalents to the mitochondria of cells in thegut, immune cells and cells of the nervous systems in thegastrointestinal tract, the nervus vagus and the brain, to generateenergy in the form of ATP (adenosine triphosphate).

It should be noted that in the prior art, it has been proposed toconsume large amounts of rapidly digestible glucose sources in order toprevent muscle catabolism and increase brain serotonin biosynthesis(Wurtman, et al, 2003, Am J Clin Nutr 77, 128-132).

The speed of release of glucose moieties in the GIT is considered to beof large interest. The way to determine the GI value is known in the artand includes measuring glucose concentration in blood during the first 2hours after oral administration of the product to be tested andcomparing the value of the area under the curve with that obtained afteradministration of glucose, which is assumed to have a value of 100. Thiscan be determined by the method described in Englyst et g Am J Clin Nutr1999, 69, 448-454.

The GI value of the digestible carbohydrate fraction is preferably lessthan 80, more preferably 20 to 72, most preferably 20 to 64. The GIvalue of the total digestible carbohydrate fraction complies with thiscriterion, though the various digestible carbohydrates in the totalfraction may demonstrate different GI values, and some may even have aGI index above 64, or even above 80. It is desired that the amount ofsuch individual digestible carbohydrates is also low. In particular theamount of free glucose in the total digestible carbohydrate fraction ispreferably less than 10 wt %, more preferably less than 4 wt % in orderto prevent a postprandial decrease of ghrelin release. The inventorsconsider a high ghrelin release after consumption of the productdesirable, for example in order to increase digestion rate of theproduct.

The digestible carbohydrate fraction preferably comprises slowly—andrapidly digestible carbohydrate. The rapid digestible carbohydrates willkeep rapidly the amount of systemic LNAA low in catabolic situations.More than 3 times, preferably more than 4 times as much weight of slowlydigestible carbohydrates should be included compared to the weight ofrapidly digestible carbohydrates. His ensures a long lastinganti-catabolic effect and a good taste of the product.

Examples of such slowly digestible carbohydrates are some starches, sometypes of large pullulan oligomers, trehalose, isomaltulose, chemicallymodified carbohydrates and several residues of digestible carbohydrates,as present in the fibre fractions used in the product, such as thecereal fibre. The speed of digestibility of the ingredients included inthe product can be measured by applying the standard method known in theart for this purpose: Englyst et al Am J Clin Nutr 1999, 69, 448-454.Those carbohydrates that are digested under these standard conditions tomonosaccharide in the period between 20 and 120 minutes after the startof the experiment were considered to be slowly digestible. Those thatwere not yet digested at 120 minutes after the start were considered tobe fibres.

The amount of digestible carbohydrates in the product usually is up to 8times, preferably up to 5 times, most preferably less than 4 times theamount of protein in order to have the largest protein effect of theproduct. Especially when it is used as a supplement, the digestiblecarbohydrates will be consumed in high amounts anyway and excessdigestible carbohydrates will impair the health of insulin-resistantindividuals, like diabetics, many obese persons and many elderly.Insulin-resistance is strongly associated with the behavioural problemswhich are aimed to be treated by the product according the invention.

It is preferred that at least part of the carbohydrates origin from thefruits of the Musa genus. Plantains and bananas can be used as source ofdigestible carbohydrates and fibres. The fruits comprise differentamount of rapidly digestible carbohydrates like sugars, dependent on thespecies and the degree of ripening of the fruit at the moment ofmeasurement or use. A typical Cavendish banana will comprise about 12.2g sugars (=about 53 wt % of total carbohydrates), 2.6 g fibre and about8 g oligomeric and polymeric carbohydrates. The fruit-derivedingredients which are preferably used in the manufacture of the productsaccording the invention comprise rapidly digestible sugars in an amountof less than 45 wt %, preferably less than 36 wt %, more preferably lessthan 18 wt % of the total carbohydrate fraction in the ingredient. Alsothe amount of rapidly digestible starch is low.

In a specific embodiment, the amount of banana-derived carbohydrates isbetween 1 and 70-preferably 2-60 wt % of the amount of digestiblecarbohydrates in the total product. Suitable ingredients include a pureeof selected fruits or an extract of the fruit. Dependant on the finalcomposition of the ready to use product different amounts of banana ordifferent qualities can be used. The banana puree can be included in acontent of 0.2 to 26 wt/vol % in the ready to use product.

The amount of digestible carbohydrates in a nutritional product (foruse) according to the invention preferably is at least 8 wt. %, inparticular 8-70 wt % of the total composition (in particular whenpresent in a ready-to-eat form). The type of digestible carbohydrates ispreferably selected on the criterion that the amount of rapidlyavailable glucose sources is relatively low, while still creating apleasant taste which is appreciated by the person that is to be treatedin accordance with the invention in particular a person who suffers froma mood—or behavioural disorder or person who is consuming a product inaccordance with the invention as a prophylactic measure to preventoccurrence of such disorder. Thus, the abundance of maltodextrins andglucose/fructose syrup, if present at all, is preferably relatively low.In an advantageous embodiment, the nutritional composition comprises oneor more slowly digestible ingredients, selected from the group ofisomaltulose (or palatinose), isomaltose and trehalose.

A preferred blend of digestible carbohydrates in the treatment of amood- or behavioural disorder complies with the following criterions:1/ the sum of maltodextrins and glucose-fructose syrup is 2-90 wt %;2/ lactose, galactose or banana puree>2 wt %;3/ the sum of isomaltulose, trehalose and isomaltose>2 wt %;4/ free fructose 1 to 8 wt %.

The type and amount of digestible carbohydrates appears to be importantnot only to provide a minimum amount of glucose and sweetness to theproduct to consume, but also to regulate the redox potential inintestinal cells, immune cells, liver cells and neurons. In anembodiment, a product according the invention aims to prevent excessformation of reducing equivalents, like NADH.

An improvement of the redox situation in the target tissue or targetcells can be measured by measuring the weight ratio of NADH to NAD+, orof NADPH to NADP+ or of derived metabolites, like lactate to pyruvate,or oxidized glutathione to reduced glutathione, as known in the art.These values can be compared with values which are obtained afterfeeding under identical conditions the products as known in the artuntil now.

It is important that the amount of NADH in the cytosol of cells in thetarget tissue has become lower after feeding a dietary fibre,combination or nutritional composition according the invention. A lowervalue will result in the end in lower expression of stress proteins,like several heat shock proteins, for example of HSPA5, or alternativestress proteins like enolase 1 and GAPDH.

The content of the digestible carbohydrate fraction in a nutritionalcomposition of the invention is usually at least 4 g per 100 g of thetotal nutritional composition, in particular at least 5 g per 100 gram,more in particular at least 8 g per 100 g. The content, in particular ina ready-to-eat product, is usually less than 80 g per 100 g, inparticular 70 g per 100 g or less, more in particular 50 g per 100 g orless.

For a liquid product, the digestible carbohydrate content is preferablyin the range of 1.5 to 9 g/100 g of the composition.

For a semi-solid product the digestible carbohydrate content ispreferably in the range of 6-30 g/100 g of the composition. For a solidproduct the digestible carbohydrate content is preferably in the rangeof 16-70 g/100 g of the composition.

The Lipid Fraction

The amount of lipids in the nutritional composition is preferablyrelatively low in order to prevent a large post-prandial PYY- and CCKrelease. In a specific embodiment this amount is less than 4 g,preferably less than 3, more preferably less than 2 g, most preferablyless than 1.7 g per dose.

The concentration nutritional composition will vary dependent on theintended serving size, but is typically less than 4 wt %. Thecontribution of the lipid fraction to the total energy as provided bythe complete formula by its protein and digestible carbohydrates can becalculated, by using the Atwater calculation which assigned theoreticalcalculation factors of 16.7, 16.7 and 37.7 kJ per gram of respectivelyprotein, digestible carbohydrates and lipids, and a contribution of zeroto other food constituents. In the products according the invention thelipid fraction will typically be in the range of 1 to 35 en %,preferably 3 to 29 en %, more preferably 5 to 22 en %.

The lipid fraction preferably comprises more than 1, preferably 3 to100, more preferably 6 to 60% of an oil comprising more than 2,preferably more than 20-g of the sum of eicosapentaenoic—anddocosahexaenoic acid per 100 g fatty acids, in order to increasesensitivity of the receptors on EE cells, the EC cells and the centralnervous system and the ENS but especially to increase dopamine releasein the nucleus accumbens and striatal regions involved in rewardsensation and motor neuron function. Important receptors which aresensitized by the product according the invention are G-protein coupledreceptors on neurons. The effects of the product on membrane functioningresult in better localization of receptors and better coupling tointracellular G proteins. This applies for example to the cannabinoidCB1 receptors.

Preferably, the lipid fraction of the nutritional composition comprises1-10 wt % of marine oil in order to help proper processing anddistribution of serotonin receptors in the body of the person that issuffering from a mood or behavioural disorder. In particular the lipidfraction contributes to the effect of the product to redistribute 5HT1Areceptors over neurons and the internalization of 5HT2 receptors inneurons, the relative expression of serotonin receptors over the organsand the vesicle-mediated release of neurotransmitters, like serotonin.

In an embodiment, the nutritional composition comprises a source ofdocosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA).

In a preferred embodiment the weight ratio of eicosapentaenoic (EPA)-and docosahexaenoic acid (DHA) in the product is larger than 0.8, morepreferably 1.0 to 30, more preferably 2.0 to 20.

Instead of the pure fatty acids also equivalents can be used which aresuitable for use in medical food and include salts, esters and ethers,including glyceride and phospholipid forms, as known in the art. Whenmaking calculations about amounts, one can assume the samebioavailability as the pure fatty acid and a contribution of fatty acidthat is similar to the amount moles of fatty acids in the completemolecule, and correcting for the weight of the complete molecule.

One important property of the lipid fraction is its ability tocontribute to the low satiating properties of the ready to use product.In an advantageous invention the nutritional composition of theinvention is suitable to induce a relatively high ghrelin response after(oral) consumption of the product. In order to contribute to thischaracteristic the lipid fraction comprises per 100 g preferably morethan 2 g octanoic acid (=C8:0) and more preferably 4 to 40, mostpreferably 8 to 20 g of octanoic acid or its equivalents (all based ontotal lipid content). Equivalents of octanoic acid are those chemicalsubstances which when consumed by humans increase the concentration inblood of compounds which comprise octanoic acid, such as triglycerides.Examples of equivalents of octanoic acid are salts of octanoate, estersor ethers of octanoic acid like acetyl-octanoate or butyl-octanoate ortriglycerides. Refined medium chain triglyceride oil was found to be agood source of endogenous octanoic acid.

The selection of amount and type of the lipids in the lipid fractionpreferably contributes to the relatively low postprandial CCK- and PYYresponse after consumption of the product. This is achieved because thelipids are easily digestible and form the right micelles in the duodenumafter release of the bile secretions. This is preferably achieved byincluding the lipid fraction in the product as small droplets that arehomogeneously distributed over the product. It is also preferred toinclude an emulsifier system which interferes as little as possible withthe emulsifying events in the duodenum. That is why the amount ofdiglycerides and especially monoglycerides is preferably relatively low.In a preferred embodiment the amount of the sum of mono and diglyceridesis less than 10, preferably less than 2 wt % of the lipid fraction. Thetotal amount of phospholipids and lyso-phospholipids usually is 0.5-12,preferably 0.7-6, more preferably 0.8 to 4, most preferably 0.8 to 3.4 gper 100 g lipid fraction.

The lipid fraction preferably facilitates modulation of the serotonergicsystem. It is therefore preferred to include a lipid fraction in theproduct according the invention which comprises a source of omega-3 longchain polyunsaturated fatty acids [(N-3) LC-PUFA's].

In order to modulate the serotonergic signalling, preferably the weightratio of long chain polyunsaturated fatty acids (LCPUFA's) of the n-3class to that of the n-6 class is 0.25-9.4, preferably 0.5 to 4. Withlong chain fatty acids is meant herein fatty acids having at least 18carbon atoms. A preferred source of n-3 LCPUFA's is krill oil thoughmore sources of omega 3 long chain poly-unsaturated fatty acids areknown in the art, like other marine oils, algae oils, fungal oil andoils derived from or extracted from genetically modified organisms,including genetically modified plants. The way such organisms should bemodified to increase the amount of n-3 LCPUFA's during their life isknown in the art and can include introduction of genes with increasedelongase- and/or desaturase activities in these organisms.

The content of the lipid fraction in a nutritional composition of theinvention is usually at least 2 g per 100 g of the total nutritionalcomposition, in particular at least 3 g per 100 gram, more in particularat least 5 g per 100 g. The content, in particular in a ready-to-eatproduct, is usually less than 50 g per 100 g, in particular 40 g per 100g or less, more in particular 24 g per 100 g or less.

For a liquid product, the lipid content is preferably in the range of1.2-5 g/100 g of the composition, more preferably 2 to 4 g per 100 gready to drink product.

For a semi-solid product the lipid content is preferably in the range of4 to 24 g/100 g of the composition. For a solid product the lipidcontent is preferably in the range of 8-40 g/100 g of the composition.

Mineral Composition:

Optionally, the nutritional composition comprises a mineral. The amountof minerals in the product can be measured as the amount of mineral ash.In order to provide the proper amount of the active mineral ions, allowa rapid digestion rate of the food constituents and induce the properpostprandial response the amount of ash nutritional product is usuallyrelatively low, at least in the form in which it is intended to beadministered (ready to use′). Preferably the amount of ash per 100 g ofliquid nutritional composition, in particular when in a ready to drinkproduct form, is less than 1.8, more preferably 0.7 to 1.7, mostpreferably 0.8 to 1.6 gram.

In a liquid nutritional composition, the ionic strength of thecomposition can play a role, in particular with respect to modulatingthe release of satiating gut hormones. A low ionic strength is thoughtto prevent too rapid release of such gut hormones. The ionic strengthcan be measured by determining the osmolarity or osmolality of theliquid product. It is preferred that the product demonstrates anosmolarity of 170 to 340 mOsm/l, more preferably 190 to 310 mOsm/l, mostpreferably 210 to 290 mOsm/l.

The amount of sodium and potassium in one ready to serve unit shouldpreferably be low, in order to decrease emesis, nausea and activation ofEC cells. The amount of sodium ions included in the compositionpreferably is less than 90 mg per 100 g, preferably 20 to 80 mg per 100g. This allows a daily consumption of less than 1500 mg per day of totaldiet.

Zinc content is preferably relatively high in order to increase theamount of ghrelin that is released after consumption of the product. Theamount of zinc in the product is preferably more than 2.4, morepreferably 3.2 to 24, most preferably 4 to 18 mg per 100 g product.Preferably the magnesium content is higher than 26 mg/100 ml or 26 mgper 100 g of the nutritional composition, in particular in a ready toeat product, more preferably 32 to 48 mg per 100 ml or per 100 g of thenutritional composition, in particular in a ready to eat product, inorder to treat deficiencies that are critical in the treatment of thediseases, while eating relatively low amounts of the product accordingthe invention. Magnesium can be included in the product as food gradeingredient as known in the art, for example magnesium sulphate ormagnesium bicarbonate.

Iron/copper ratio is preferably high to prevent deterioration in theproduct and increase metabolic pathways which support serotoninsignalling and tryptophan metabolism. Preferably the weight ratio ofiron to copper in the nutritional composition, in particular in a readyto use product, is more than 10, more preferably 12 to 40, mostpreferably 14 to 28. The amount of iron ion in the nutritionalcomposition preferably is in the range 0.1 to 15 mg per 100 g product,more preferably 0.3 to 7 mg per 100 g product, most preferably 0.6 to 3mg per 100 g product, in particular for a ready-to-drink product. Thestated upper limit for the iron is in particular relevant in order toprevent instability in the product and entrance of iron salts in thecolon. The iron ions preferably have the form of ferrous ions. The ionsmust be bound to anions which allow rapid dissolution in the gut andallow high bioavailability of iron. Suitable anions to achieve this areorganic acids like sulphate, or gluconate, ascorbate and amino acids,like glycine or alanine.

One can distinguish between buffer strength and buffer capacity of aproduct, as is done in WO2012/092082. The buffer strength is defined asthe number of millimoles of HCl (hydrogen chloride) that is needed tolower the pH of 50 ml of the ready to use liquid formula from 6.00 to3.00. The buffer capacity of the nutritional composition can be measuredby methods known in the art, which include titration of composition Thebuffer capacity is expressed as the increase in proton concentration(1-1+) or change in pH, following the addition of a selected amount ofacid.

For dry products a solution/emulsion is made of 10% of dry product inwater to a volume of 100 ml water.

In a preferred embodiment, the ready to use liquid medical food has abuffer strength of less than 8 mMoles HCL, more preferably 1-6 mMolesand most preferably less than 3 mMoles HCL.

In a preferred embodiment the buffer capacity of the product isespecially low in the pH range 2 to 7.4. This is preferably achieved byselecting ingredients with a low buffer capacity. This applies to themacro-ingredients, for example the proteins, but also to the type ofminerals. The type of anions is therefore not an organic acid orphosphate, which are known to have a high buffer capacity. Insteadsulphate, chloride or nitrate, or to a small extent, bicarbonate is usedas counter ion in the mineral salts. In a preferred embodiment of themineral fraction of the nutritional composition according the inventionis the weight amount of the sum of sulphate and nitrate 0.05 to 20,preferably 0.08 to 2 times the weight amount of phosphates. The weightamount of phosphates is the anion part of the mineral-phosphates thatare included in the product. The concentration of phosphorus in theproduct is defined by applying the criterion that preferably is lessthan 14 mg per g protein fraction.

Other Components

Several other components are useful to improve the effect of the activeingredients. According the inventors in particular one ore more othercomponents may be included to maintain or improve the action of the mostrelevant endogenous proteins involved in tryptophan catabolism andserotonin handling, in vivo. These proteins include aromatic L-aminoacid decarboxylase, kynurenine hydroxylase, and the expression orlocalization of one or more serotonin receptors and proteins involved inthe release of neurotransmitters, like serotonin, but also dopamine.

In a preferred embodiment, a composition (for use in accordance with theinvention) comprises folate (vitamin B11). The content/dosage ispreferably relatively high in order to allow rapid catabolism oftryptophan through the kynurenine pathway when needed, and subsequentlystimulate neurogenesis and synaptogenesis and microglia function. Theinventors believe that the latter phenomena can be explained by theimprovement of nucleotide metabolism by the product according theinvention. Folate can be included in the product in a form thatincreases systemic folate concentrations after oral administration.These forms include food grade qualities of folate monoglutamate,folinic acid and one-carbon-substituted folates and polyglutamate formsof these folates. The amount of folate in one dose of (ready to serve)product according the invention is preferably 0.05-4, preferably 0.1-3times the recommended daily allowance values of the FDA 1989.

Vitamin B6 is preferably included in a composition (for use) accordingto the invention, in order to prevent accumulation of undesiredmetabolites of dietetic tryptophan when catabolised through thekynurenine pathway. Suitable sources of vitamin B6 include pyridoxine,pyridoxamine, pyridoxal and pyridoxal phosphate, in free form or ascomplex with other molecules like amino acids or peptides. The amountsto include are 0.05 to 4, preferably 0.1 to 3 times the recommendeddaily allowance values, as disclosed in 1989 by the RDA.

Though the kynurenine pathway is stimulated through inclusion of folateand vitamin B6, and this would result in additional synthesis ofnicotinamide nucleotides (NAD+, NADH and NADPH and NADP+), for somesubjects it can be advantageous to include vitamin B3 in the products.Suitable forms of vitamin B3 include niacin (nicotinic acid, NA), itssalts or esters, and niacin mononucleotide. Suitable daily dosages are0.1 to 3, preferably 0.15 to 2 times the daily dosage as recommended perday (RDA, 1989 values).

It is preferred to use niacin (NA) or its salts or esters as source ofvitamin B3 above nicotinamide. Though it may induce flushes at lowerdoses compared to its amide form, and may induce a shorter and moretransient increase of systemic NAD+ concentrations, it is preferredbecause the amide form can freely pass the blood brain barrier and thehigh concentrations of niacinamide will disturb NAD+ metabolism andcholine metabolism in brain, while not being capable of potentiallybeing converted to NAD+ (nicotinamide adenine dinucleotide). It istherefore preferred to keep the dose of vitamin B3 per serving unitbelow a threshold value of 2 times, preferably below 1.0 times the RDAvalue, when the source of vitamin B3 is niacin, in order to have anundisturbed and maximal biosynthesis rate of NAD in the brain.

Though the biochemical pathways in the brain are of paramountimportance, the inventors believe that the hepatic processes alsodetermine brain serotonin handling due to the passage of kynurenine and3 hydroxy kynurenine, but not quinolinic acid and kynureninic acid overthe blood brain barrier.

Hydroxylation of kynurenine is catalyzed by kynurenine mono-oxygenase(KMO) in rat brain and is a main step away from the KYNA pathway (whichis katalyzed by the aminotransferase KAT-2) and into the biosynthesis ofquinolinic acid and NAD. The inventors consider it to be advantageousthat this step can occur in a sufficient amount and it is thereforepreferred to include additional vitamin B2 in the formula. Suitableforms of vitamin B2 include food grade qualities of riboflavin orriboflavin which is non-covalently bound to other molecules likepeptides or proteins. The amount to include is usually 0.05 to 4 times,preferably 0.1 to 3 times the recommended daily allowance as disclosedby the FDA in 1989.

In addition food grade bioavailable iron ions may be included in thecomposition, preferably in an amount of 0.1-10 times the recommendeddaily allowance as published by the Food and drug administration in theUSA in 1989. The amount of iron ion in the nutritional compositionpreferably is in the range of 0.1 to 15, most preferably 0.3 to 7 mg,most preferably 0.6 to 3 mg per 100 g product, in particular per 100 gready-to-use product.

The quinolinic acid (QA) pathway could result in toxic amounts of QA.The inventors have aimed to prevent this by increasing the rate ofphosphoribosylation of QA by providing support to the5-phosphoribosyl-1-pyrophosphate (PPRP) synthetase. This is achievableby supporting the generation of adenosine triphosphate (ATP) through thecomponents in the composition, in particular through several of thetrace elements (vitamins and minerals) in the composition.

The inventors find it important that digestible carbohydrate fraction inthe product provide sufficient reducing equivalents in the form ofNADPH+ in order to allow this selective form of the kynurenate pathway.A selective increase of the QA pathway at the cost of the biosynthesisof kynurenic acid (KYNA) may induce an enhanced release ofneurotransmitters in general, including dopamine, serotonin, glutamateand gamma-aminobutyric acid, as a consequence of increased activation ofnicotinic receptors in the brain. This applies in particular to thehomomeric nicotinic receptors, like the homopentamer alpha-7 nicotinicreceptor in brain.

The inclusion of vitamin B6 contributes to the capacity to get rid ofexcess quinolinic acid wherein catabolism to NAD is impossible orundesired, which may occur in impaired phospho-ribosylation as duringenergy deficiencies.

Choline or betaine is preferably included in the product. However, theamount should preferably remain relatively small in order to preventtrimethylamine oxide formation. This is achieved by selecting aconcentration range of 12 to 120 mg per 100 g of the nutritionalcomposition (in particular in a ready to serve product).

In addition, preferably a (rapidly available) compound is included whichprevents that the microflora of the colon can come into contact with thedietetic choline or betaine. Suitable choline compounds are rapidlyabsorbed in the small intestine and include choline alfoscerate andciticoline. Salts of choline with organic acids are preferably avoided.However, preferably eutectic solvents of choline chloride with urea,zinc chloride, glycerol or mixtures thereof are included as cholinesource. These eutectic solvents can be manufactured using proceduresknown in the art, e.g. by combining the proper molar amounts andblending at the right temperature above the melting point of theeutectic solvent to manufacture. Using a facilitator, like a primaryamount of solvent prior to addition of the new reagents is preferred.

The changes in serotonergic systems as induced by a product of theinvention also increase the effects of the orally administered inositolcompounds. In a particular embodiment according the invention aninositol compound is included in the nutritional composition. In apreferred embodiment the inositol is selected from scyllo-inositol,myo-inositol or chiro-inositol. Suitable sources for these activecomponents include the free substances as isolated from natural sourcesor the chemically synthesized and purified food grade compounds.Suitable amounts of inositol are about 0.05 to about 1 g inositol per 20to 120 g of the composition (in particular as ready to serve product). Apreferred dosage or preferred amount inositol compound in a serving unitis 0.05-1 g.

The vitamin D content is preferably 1.3 to 40, more preferably 1.8 to34, most preferably 2.0 to 28 microgram per 100 g of the composition (inparticular as ready to eat product) in order to combat deficiencies thatare critical in the treatment, while eating relatively low amounts ofthe product according the invention. As vitamin D ingredient the foodgrade synthetic compounds or isolates as known in the art can be used.It is preferred to use vitamin D3 as ingredient.

It is preferred that the amount of quinones, in particular PQQ in theready to serve product is more than 5 mg, more preferably 10-2000, mostpreferably 20-1000 mg per 100 g composition (in particular as ready touse product).

Ascorbic acid or an equivalent is preferably included to ensure properintake to ensure support of several oxidation (or hydroxylation)reactions in neurotransmitter metabolism, both in the enteric—and thecentral nervous system. Suitable equivalents or food grade ingredients,like ascorbyl esters, for example esters with organic acids like fattyacids, acetate, butyrate, amino acids, ethers with carbohydrates andsalts or esters of ascorbate, like respectively potassium ascorbate andethyl ascorbate respectively.

The following table provides preferred dosages of vitamins andmiscellaneous ingredients. A product according the invention preferablycomprises at least two ingredients of Table 1, next to folate (vitaminB11).

TABLE 1 Preferred Amount Ingredient/ (x RDA 1989) component Preferredsource per serving size Vitamin B11 Non-methylated mono- 0.05 to 4glutamate forms Vitamin B6 Pyridoxamine 0.05 to 4 Vitamin B3 Niacin(nicotinic acid)  0.1 to 2 Inositol Myo-inositol   0.05 to 1 g Choline,Eutectic fluids of choline, 12-120 mg betaine choline alfoscerateciticoline quinones PQQ, menaquinones 0-2000, more preferably 5-2000 mgOsmolality 210-290 mOsm/l Vitamin D Vitamin D3 18-40 ug Iron Ferroussulphate, ferrous 0.5-15 mg gluconate, ferrous chelates with amino acidscholesterol Cholesteryl esters, 0-2000, more cholesterol preferably10-900 mg Vitamin C Ascorbic acid, its salts in 0.02 to 6, more oxidizedor reduced form, preferably 0.1 to 3 ascorbyl esters.

Advantageously, after consumption of a liquid product, the productshould remain fluid once it has entered the stomach or ileum in order toallow rapid mixing with digestive juices, which include proteases,amylases lipases and buffering agents. This allows rapid digestion ofcomponents of the product and absorption of the active components by thefirst part of the GIT.

It is preferred to bring the product in a taste which is appreciated bythe consumer and supports food consumption. This is preferably achievedby decreasing the activation of vanillin receptors. In a preferredembodiment the amount of vanillin is that low that activation does notoccur in a relevant or significant degree, e.g. by avoiding theinclusion of vanilla flavours in the product according the invention.

Product Form, Energy Density, Dosing Unit Size

The fibre, combination or nutritional composition (for use) accordingthe invention can be used as food supplement or as product fortherapeutic—or pharmaceutical intervention. The nutritional compositioncan be also be provided in the form of a complete nutrition. The fibre,combination or nutritional composition can be provided in any productform, in particular as a ready-to-use product or as a concentrate thatis diluted, e.g. with water or by blending it with a food product.

The products can have a liquid, semi solid or solid nature, depending onpalatability requirements or desires of the intended user.

In accordance with the present invention, liquid products are typicallyproducts that are pourable (at 20° C.), in particular pourable from anopened container in which they are contained, or that can be withdrawnfrom a container by sucking (by a person consuming the liquid) through astraw or drunk directly from an opened container. In particular, aproduct is considered to be liquid or pourable if its viscosity, asmeasured using the method as described in the definitions section, liesbelow 200 mPa·s. Within the context of the invention, the viscosity isthe viscosity as measurable using an Anton Paar Physica MCR301 rheometerwith a CP50-1/PC cone (diameter 50 mm, 1° difference between middle andoutside) at 20° C. at 100 s⁻¹. In particular for a liquid product thatis intended for administration by drinking, or via a straw or tube, theviscosity preferably is 100 mPa·s or less. In a particularly preferredembodiment, the viscosity is 40 mPa·s or less. In a preferredembodiment, the viscosity of a liquid product according the invention asstored before consumption is 1 to 24 mPa·s, in particular 1-20 mPa·s.

As used herein ‘semi-solids’ generally are nutritional productscomprising 20 to 82 wt % dry mass, in particular 25-75 wt. %. Dry massis defined as the amount of product that remains after drying under theconditions as recommended for that particular food product according torecognized methods as e.g. published most recently, prior to theeffective filing date of the present disclosure by the AmericanOrganization of Analytical Chemists. In particular, semi-solids have aviscosity that exceeds the viscosity of a liquid product. Typicalexamples of semi-solids are puddings, gels, porridges, ice-cream,sandwich spreads, pastes, and products having a similar rheologicalconsistency.

As used herein solids are products comprising less than 18 wt % ofwater. Typical examples of solids are powders, food-bars (such asgranola bars, candy bars), and the like.

A product (for use) according the invention, in particular a nutritionalcomposition, usually has an energy density (ED) in a specific range inorder to provide the efficacy without the adverse effects on theintestinal systems. For liquid products the ED is usually more than 1.6,preferably at least 3.2 kiloJoule per gram product, in particular pergram ready to use product.

In a preferred embodiment, the nutritional composition of the invention,in particular a ready to use product or a concentrate, has an energydensity of more than 1.67 kJ per gram product, in particular of 3.14 kJper gram or more, the composition comprising

a tryptophan source providing more than 2 mg tryptophan per gram of thetotal composition, preferably 3-60 mg tryptophan per gram of the totalcomposition;

a peptide comprising at least 7 amino acids, which peptide may be atryptophan source; and

a dietary fibre fraction comprising dietary fibre molecules as mentionedherein.

In particular for a ready-to-eat liquid product, the ED may inparticular be 6.7 kJ/g or less, more in particular 4.6 kJ per g or less.

If the product is semi-solid, in particular when having a dry mattercontent of 20-60 g per 100 g (ready to serve) product, the ED ispreferably in the range of 19.2 to 52.8, preferably 26.3 to 46.1 kJ per100 g (ready to serve) product.

The energy density of the solid product should generally be less than 20kJ per g (ready to serve) product.

If the nutritional composition is to be used as a (significant part ofthe) diet by the subject to be treated with the composition, the EDshould generally exceed the minimum value of 3.2 kJ/g because it shouldprovide energy to the patient to prevent a lack of glucose or othermetabolic energy substrates in blood or tissue, which would supportprevalent catabolic processes and the subsequent loss of lean body mass.This overall decrease of catabolism is relevant for tryptophan andserotonin metabolism, because during muscle catabolism branched chainamino acids will be released into the blood, which may impair tryptophanpassage over the blood brain barrier. Subsequent conversion oftryptophan into serotonin in the brain can become less, due to lack ofsubstrate. This adverse effect is avoided or at least reduced by asufficiently high ED.

The decrease of catabolic reactions is in particular achieved by acombination of technical features as claimed, so not only by energydensity. It is contemplated that a product of the invention may inparticular have an ability to decrease the degree of phosphorylation ofPKR or eIF2-alpha, which decreases the degree of ubiquination ofintracellular proteins through interaction with FOXO or NFkappaB.

The components in a product (for use according to) the inventionpreferably support energy metabolism and the induction of a beneficialepigenetic condition of nuclear histones to allow a sufficient rate oftranscription of the genes of microglia and intestinal immune cells andof neurons that are relevant to for example immune function and thebiosynthesis of enzymes involved in tryptophan metabolism and ofneurotransmitter receptors.

The maximum value for the energy density (ED) is usually determinedconsidering the volume of product that should be consumed in order toinduce the efficacy as claimed, while both ED and the amount of foodthat is consumed determine the postprandial physiological response tothe consumption activity. This response includes a volume-relatedresponse of the GIT through activation of the ENS or entero-endocrinesystem, which not only regulates digestion, but also satiety and foodintake. Therefore values of the energy density of the product preferablyare to be considered in combination with the relatively low volumes thatare consumed per consumption event. By adding new consumption eventswith again low volume portions, the efficacy that is aimed for can beobtained.

Conventional food products are typically packed in all possible sizes inorder to suit the needs of customers. In the present invention thevolume is preferably restricted and coupled to the maximal energydensity in order to achieve the efficacy.

Thus, in an advantageous embodiment of the invention, the amount of foodand energy that is consumed per serving does not exceed a certainthreshold value. This value is determined by the subject's capacity todigest the food properly, and to prevent activation of an excessivepostprandial 5HT response in the lower gut, and to prevent activation ofthe release of a wide range of anorexic peptides, like PP, PYY andothers.

In a specific embodiment the amount of the composition which isadministered does not exceed 510 kJ per serving size and preferably isin the range of 65 to 9380 kJ, more preferably 75 to 294 kJ. This can beachieved by packaging a ready to use amount in a package size which issufficiently small. In order to have a convenient package size, thisshould not be too small, i.e. more than 5 g, preferably 12-130 g, morepreferably 18-90 g, most preferably 20-70 g for liquid and semi-solidproducts. Administration of the active components in a solid matrix isusually provided in a small size, so less than 10, preferably less than5 g per serving size, in order to prevent overeating which would impairdigestion rate and induce activation of the EC cells in the lower partsof the GIT. In addition the solid products have preferably been preparedsuch that the serving units rapidly will disintegrate once they enterthe stomach. Disintegration should preferably not be achieved by usinginclusion of highly buffering substances.

The components in the product determine in what form energy is providedto the organism and details will be described in the relevant clauses.

In a preferred embodiment, the nutritional composition is a ready-to-eatproduct, i.e. a product that is suitable for consumption without addingfurther ingredients or further processing (except for additional heatingto a desired serving temperature). Examples of preferred embodiments areliquids and extruded dry products or bars.

In another preferred embodiment, the nutritional product is aconcentrate, which is intended for reconstitution in water or anotherdrinkable liquid or for blending with another nutritional product.

In a specific embodiment, the product is a sterilized liquid orsemi-liquid product, in particular a product sterilised with UHT (soabove 121 C) at pH2-7.5, preferably 2.6-7.0.

The invention further relates to a packaging, in particular a unit-dosepackaging, comprising 5-300 g, preferably 12-130 g of a liquid orsemi-solid nutritional composition according to the invention.

The invention further relates to a packaging, in particular a unit-dosepackaging, comprising 0.5-10 g of a solid composition according to theinvention.

In accordance with the present invention, liquid products are typicallyproducts that are pourable (at 20° C.), in particular pourable from anopened container in which they are contained, or that can be withdrawnfrom a container by sucking (by a person consuming the liquid) through astraw or drunk directly from an opened container. In particular, aproduct is considered to be liquid or pourable if its viscosity, asmeasured using the method as described in the definitions section, liesbelow 200 mPa·s. Within the context of the invention, the viscosity isthe viscosity as measurable using an Anton Paar Physica MCR301 rheometerwith a CP50-1/PC cone (diameter 50 mm, 1° difference between middle andoutside) at 20° C. at 100 s⁻¹. In particular for a liquid product thatis intended for administration by drinking, or via a straw or tube, theviscosity preferably is 100 mPa·s or less. In a preferred embodiment,the viscosity of a liquid product according the invention as storedbefore consumption is 1 to 24 mPa·s.

As used herein ‘semi-solids’ are nutritional products comprising 32 to82 wt % dry mass. Dry mass is defined as the amount of product thatremains after drying under the conditions as recommended for thatparticular food product according to recognized methods as e.g.published most recently by the American Organization of AnalyticalChemists. In particular, semi-solids have a viscosity that exceeds theviscosity of a liquid product. Typical examples of semi-solids arepuddings, gels, porridges, ice-cream, sandwich spreads, pastes, andproducts having a similar rheological consistency.

As used herein solids are products comprising less than 18 wt % of water(moisture). Typical examples of solids are powders, food-bars (such asgranola bars, candy bars), and the like.

In a specific embodiment, the food product is a medical food. A medicalfood preferably comprises at least 0.7 g fibre per 100 g product. Thefibre preferably content preferably is 0.8 to 1.2 g fibre/100 g for tubefeeding. The fibre content preferably is at least 1.2 g to 4.2 g per 100g sip (or drink) feed.

The protein content of a medical food preferably is less than 10 g, morepreferably less than 8.2 g, most preferably less than 6.3 g per 100 gproduct. Preferably, the medical food has a low glutamine content in theprotein fraction, i.e. less than 10 g, preferably 3-9 g per 100 gprotein fraction.

The amount of added organic acids in a medical food of the inventionusually is less than 0.3 g per 100 ml, preferably less than 0.26 g, morepreferably 0.02-0.18 g/100 ml (is declared as “others” in digestiblecarbohydrate fraction).

Method of Treatment

The invention further relates to a method for prophylactically ortherapeutically treating a human in need thereof, the treatmentcomprising administering an effective amount of a dietary fibre, incombination with a pharmaceutical composition or a nutrition as definedin any of the preceding claims, thereby reducing or avoiding theoccurrence of a negative gastro-enteric side-effect of a composition,preferably a medical nutrition or a medicament. The negative side effectpreferably selected from those mentioned herein above, in particular,the negative side-effect is a premature sating effect.

In an embodiment, in the method of treatment, the dietary fibre,combination or nutritional composition is administered in a dosageproviding 502 kJ or less, in particular in a dosage providing 20.9-502kJ.

In an embodiment, in the method of treatment the subject in needthereof, is a human, preferably a human having an age of at least 1years, in particular a human having an age of 2 to 85 years.

In particular, in a method according to the invention the dietary fibre,combination or nutritional composition is administered orally oradministered into the gastrointestinal tract in another way, such as bytube-feeding.

When referring herein to a treatment, this generally includesprophylactic treatments and therapeutic treatments, unless specifiedotherwise. A prophylactic (preventive) treatment generally is aimed atreducing the chance that the treated subject develops a trait,impairment, symptom, disease, side-effect, syndrome or disorder. Theeffectiveness of a prophylactic treatment can e.g. be determined bycomparing the probability that a specific trait (etc to disorder)develops in a sufficiently large in a double blind way according theprinciples of Good Clinical practices, wherein one part of the group istreated according to the invention and another part is treated with aplacebo for a relevant period of time. The skilled person will be ableto define suitable conditions for the study, depending on the intendedeffect.

EXAMPLES Example 1

Ready to eat semi-solid product (pudding, porridge or ice cream orsandwich spread or paste or sauce). The product can in particular beused by toddlers & children in the age range of 1-12 year in amountswhich are voluntarily acceptable.

TABLE 2 Components Quantity per 100 g Dry matter is 25 to 75 g per 100 gproduct ready to eat product Protein fraction 8-20 g Of which intactprotein 5-19.9 g Tryptophan as free amino acid or peptide = 0.1-3 gDigestible carbohydrates 8-20 g Of which maltodextrins are less than 90wt % Glucose/fructose syrup less than 80 wt % Lactose or galactose orbanana puree >2 wt % The sum of isomaltulose, trehalose andisomaltose >2 wt % Lipids 8-24 g Of which marine oil 1-10 wt % andphosphatidylcholine is <41 wt % Fibre: 6-24 g Cereal fibr xylan enrichedfractions Of which beta-glucans are >1 wt % Acetogenic fibres likeinulin and fructo- oligosaccharides are less than 85 wt % of fibrefraction Vitamin blend comprising at least 2-30 microgram vitamin D PQQ20-1000 mg Mineral premix comprising at least 6-20 mg magnesium Optionalmanufacturing aids, colorants, flavours etc. Water makes up the finalweight of the product

Example 2

Dry product (moisture content is less than 14 wt % in the ready to useproduct). The product can in particular be used by an adult.

TABLE 3 Components; Dry matter is 86-98 g per 100 g Quantity per 100 gproduct; the remainder being water ready to eat product Protein fraction14-40 g Of which intact protein 11-39.6 g Tryptophan as free amino acidor as dipeptide = 0.4-3 g Digestible carbohydrates 16-70 g Of whichmaltodextrins are less than 90 wt % Glucose/fructose syrup less than 80wt % banana puree The sum of isomaltulose, trehalose and isomaltose >2wt % Starch >2 wt % fruit may provide some glucose and fructose Lipids8-40 g of which marine oil 1-10 wt % Fibre: 6-40 g Cereal fibrefractions Of which beta-glucans are >1 wt % and xylans are >60%Acetogenic fibres like inulin and fructo- oligosaccharides are less than35 wt % of fibre fraction Vitamin blend comprising at least 2-30microgram vitamin D Mineral premix comprising at least 6-20 mg magnesiumOptional manufacturing aids, colorants, flavours etc. Water makes up thefinal weight of the product

Example 3 Liquid Product

TABLE 4 Concentration per 100 g ready Component Energy density = 2.5 to6.8 to use product kJ/ml (density = 1.1 g/ml) Protein 5-9 g Comprising5-95 wt % proteins from whey or vegetable origin and more than 1 wt %added free L-tryptophan Lipids 2-5 g Of which DHA is 0.5-4 g per 100 gfatty acids Rape seed lecithin is 10-40 wt % Fibre 2-15 g Rice fibre wt60% partially hydrolyzed guar gum 20 wt %, acacia gum (hydrolyzed 20 wt%) Digestible carbohydrates 4-12 g Miscellaneous Vitamin and mineralpremix complying with the claim requirement

Example 4 Isolation of an Active Dietary Fibre

Isolation of the rice bran is done by de-hulling the rice grains,grinding and sieving them. The flour is separated from the fibrefraction.

The rice bran can be further purified by washing it with an alkalineaqueous solution to remove digestible carbohydrates and part of thesoluble fibre. Both fractions are of value.

The soluble parts can be subjected to an hydrolysis step using one ormore enzymes to decrease molecular weight of the residual fibre, toremove part of the substituents or ferment part of the digestiblecarbohydrates.

The insoluble parts, when isolated can be subjected to enzymatichydrolysis to decrease molecular weight and increase solubility.

Example 5 Method to Measure Effect on Satiety of the Dietary Fibre

The satiety is measured using a method as disclosed below in acomparative product without the fibre and a product in which aneffective amount of the fibre has been included but which is otherwisethe same as the comparative product.

The determination of the sating properties of the product can be done bymeasuring the intensity of one or more sating signals during the first 2hours after consumption. Suitable biomarkers in blood for such satingsignals include of specific sating peptides like CCK, GLP-1, PYY orother parameters known in the art. Measurement of AUC or the releasepattern for the first 2 hours allows justified comparison. Alternativelyserotonin released in the full blood or blood platelets can be measured.

Stanley et al 2005 Physiol rev 85, 1131-1158 disclose the neuropeptideswhich are modulating food intake and satiety and refer to methods tomeasure their postprandial release. In addition the methods as appliedin Blom et al, 2005, Am J Clin Nutr 83, 211-220 and in Karhunen et g,2010 J Nutr, 140, 737-744 can be applied. Obviously the very highviscosity and unpalatability of psyllium as tested by Karhunen make theuse of psycllium unsuitable in the manufacture of medical nutrition. Inthe latter study the choice for this fibre complicated the relationbetween the concentration of endogenous neuropeptides and desire to eat,hunger, satiety and related phenomena.

When a significant difference is measured between the product with andwithout the fibre the effect on satiety was considered to be convincing.

The duration of satiety becomes a relevant parameter 2 hours afterintake. Proper questionnaires/interviews to assess desire to take newproduct or feelings of fullness can be applied. Alternatively the momentof voluntary start of consumption of new food can be measures as well asthe amount of food that is consumed voluntarily at a fixed time 2-4hours after intake of the first product. When the urge to eat againwould come 10 minutes earlier after consumption of the product withfibre, compared to the product without fibre the fibre is defined tohave a inhibiting effect on satiety

Example 6 Multifibre Blend

TABLE Preferred fibres blends with fibres from different sourcesPreferred Preferred Examples of origin in Preferred amount in Classorigin blend origin (1) blend Cereals Rice, oats, corn, X Rice, wheat,30-80 wheat, rye, oats barley, triticale, amaranth, millet/quinoa Fruit/Banana/plantain Banana/ 0-30. Though vegetables varieties, apple,plantain optional in citrus, prune, this embodi- cabbage, tomato, ment,1-20 is squash, sugarcane included in bagasse the most preferred oneRoot/ red beet (beta X Chicory, 10-60 tubers vulgaris), sugar beet beet,potato, chicory, onion Beans/ pea (e.g. pisum X Pea, soy  2-30 pulsessativum), soy, Azuki beans, Phaseolus varieties (e.g. vulgarus), lupinGums Acacia, guar, X Acacia, guar,  2-18 Konjac and/or or Konjac chiagum. (2) Resistant starches from a X Rice bran or  3-35 starch cereal(e.g. corn, alternative wheat, rice), source to potato or tapioca meetcriteria of (3). Optional a/fibres derived 0-40 (most from oil seeds orpreferred 3-15) nuts, for example sunflower seeds and/or flaxseed orb/polydextrose (e.g. Litesse) or oligosaccharides e.g. fructo orgalacto- oligosacchraides. Sum Blend X 100 Legend to the table: (1) thenumbers added refer to technical features which are independent of thepreferred origin of the fibre, in order to mimic functionality of thefibre as isolated from the plants: (2) Preferably these gums have beenpartially hydrolyzed. More preferably this hydrolysis is to a degreethat more than 60 wt % of the gum fibre has a degree of polymerizationof 3 to 20. (3) More than 60 wt % of the starch particles have a sizebetween 2 - 15 micron. (4) Amounts are expressed as wt % of the totalfibre blend. (5) commercial sources have been disclosed in thedescription. Preferred commercial fibre ingredients include for ricefibre Beneo and Biobran, for resistant starch Novelose, for soy Fibrim,for oats Vitacel, for PHGG Nutricource, for acacia Benecke, for sugarbeet Fibrex, for wheat bran Ultracel, for polydextrose Litesse, forinulin raftiline and for and for. These are all registered trademarksand the information about proprietor and technical properties findablethrough the intranet. . . .

Example 7 Multifibre Blend

Cereal fibre other than resistant starch: 4-50 wt % (rice, wheat, oats,corn)Resistant starch: 3-50 wt % (derived from rice starch)Fibre from tubers or roots: 5-60 wt % (onion, chicorei, sugar beet,potato)Fibre from pulses or beans 2-40 wt % (soy, pea, lupin), andFibre from vegetable leaves or fruits (banana, apple, citrus fruit):2-40 wt %Optionally hydrolyzed fibres (fructo-oligosaccharides,galacto-oligosaccharides, which may be comprised in any of the abovefibres, except for ‘resistant starch’.)

Example 7 Measurement of Early Activation of EC Cell Mediated

In vitro model: the amount and rate of serotonin that is released byenterochromaffin cells is measured, after exposure to a physiologicalrepresentative sample of the product with and without the active fibre

In an animal model (rats) serotonin release after consumption of thefood is measured in blood or in the gut tissue ex-vivo. The activity ofthe enteric nervous system after food intake can be measuredalternatively. The products according the invention will decreaseoverall release of serotonin and activation of the ENS. The satingproperties of the product can be measured as well in animals

Example 9 Medical Nutrition Comprising Multifibre

liquid suitable for use as complete medical nutrition, comprising per100 ml

Protein: 4.0 g

Digestible carbohydrates: 12.1 g,organic acids<0.2 g

Fat: 3.9 g

Dietary fibre=1.5 g, consisting of a rice fibre (other than resistantstarch), resistant starch, inulin and soy fibreThe amounts of minerals (Na, K, Cl, Ca, P, Mg), trace elements (Fe, Zn,Cu, Mn, F, Mo, Se, Cr, I) and vitamins (A, B1, B2. B3. B5, B6, B11, B12,D, biotin) that are included comply with recommendations and FSMP rules.Choline=37 mg, carotenoids=0.3 mg

Example 10 Medical Nutrition Comprising Multifibre

Liquid suitable for use as a supplement

Protein: 6 g

Digestible carbohydrates: 18.0 gorganic acids 0.4 g or less

Lipids: 5.8 g

Dietary fibre: 2.25 g, wherein the fibre comprises rice fibre (otherthan resistant starch), resistant starch, beet fibre, and banana fibreThe amounts of minerals (Na, K, Cl, Ca, P, Mg), trace elements (Fe, Zn,Cu, Mn, F, Mo, Se, Cr, I) and vitamins (A, B1, B2. B3. B5, B6, B11, B12,D, biotin) that are included comply with recommendations and FSMP rules.

Choline=55 mg. Example 11

Medicament comprising 2-100 mg of a serotonin-reuptake inhibitor (SSRI)and 2 g of rice fibre consumed in association with the intake of theSSRI. Examples are Citalopram and Fluoxetin.

1. Dietary fibre, for use in delaying or otherwise reducing a satingeffect of a medical nutrition or of a medicament, wherein the dietaryfibre is cereal dietary fibre and the medical nutrition or medicament isfor oral or gastro-enteric administration by a human.
 2. Dietary fibrefor use according to claim 1, wherein the cereal dietary fibre comprisescereal fibre selected from unmodified and modified rice fibres. 3.Dietary fibre for use according to claim 2, wherein the cereal fibre isa rice fibre, provided as rice bran, preferably a rice bran combinedwith rice germ.
 4. Dietary fibre for use according to any of thepreceding claims, wherein the medicament is a drug having an inhibitoryaction on serotonin reuptake, an inhibitory action monoamino oxidation,or an opiate.
 5. Dietary fibre for use according to any of the precedingclaims, wherein the dietary fibre is for at least 15 wt. % composed ofnon-acetogenic saccharide units, preferably for at least 60 wt. %composed of non-acetogenic saccharide units, in particular for at least90% composed of non-acetogenic saccharide units.
 6. Dietary fibre foruse according to any of the preceding claims, wherein the nutritioncontains less than 0.3 g per 100 ml added organic acids, preferably lessthan 0.26 g, more preferably 0.02-0.18 g/100 ml.
 7. Dietary fibre foruse according to any of the preceding claims, wherein at least 8 wt. %of the dietary fibre is formed of insoluble fibre molecules, preferably18-72 wt. %.
 8. Dietary fibre for use according to any of the precedingclaims, comprising a fibre selected from the group of, xylans,celluloses, hemi-celluloses, beta 1-3 glucans, and lignins.
 9. Dietaryfibre for use according to claim 8, wherein, the dietary fibre comprisesan arabinoxylan.
 10. Dietary fibre for use according to any of thepreceding claims, wherein the fibre comprises beta-glucans, of which atleast 40 wt. % is selected from insoluble beta-glucans and non-branchedbeta-glucans.
 11. Dietary fibre for use according to any of thepreceding claims, wherein the fibre forms part of a fluid compositionhaving a viscosity of less than 30 mPa·s at shear rate of 20 at atemperature of 20° C.
 12. Dietary fibre for use according to any of thepreceding claims, wherein the dietary fibre is to be administered orallybefore or together with said medicament or nutrition.
 13. Dietary fibrefor use according to any of the preceding claims, wherein the human tobe treated is selected from the group of hospital patients, oncologypatients; persons that that are subjected to chemotherapy; persons thatare subjected to radiotherapy; institutionalized persons; individualswho experienced stroke or cerebro- or vascular problems; dementedpersons; persons who experience taste or smell deviations; individualswho are physically impaired such as having a physical handicap, visualimpairment, or essential tremor; individuals who have experienced atrauma; persons recovering from surgery; persons experiencinginflammatory processes, such as persons who suffer from an inflamed gut,mucositis or irritated bowel; humans depression, humans having autism,humans having Parkinson's disease, humans suffering fromobsessive-compulsive disorder, malnourished people and elderly people.14. Dietary fibre for use according to any of the preceding claims,wherein the fibre—when administered to a human—is a stimulant of a GPR43receptor.
 15. Dietary fibre blend, optionally for a use as defined inany of the preceding claims, the blend comprising cereal fibre otherthan resistant starch and gum, and a fibre from at least two, inparticular at least three, of the following groups: gums; fibres fromtubers or roots preferably other than resistant starch and gums; fibresfrom pulses or beans preferably other than resistant starch and gums;and fibres from vegetable leaves and fruits preferably other thanresistant starch and gums.
 16. Dietary fibre blend according to claim15, further comprising resistant starch.
 17. Dietary fibre blendaccording to claim 15 or 16, wherein—if present—the weight percentage offibres from said groups, based on the total weight of fibres, is 20-80wt % for the cereal fibre: 3-50 wt % for resistant starch: 5-60 wt % forthe fibre from tubers or roots: 2-40 wt % for the fibre from pulses orbeans; 3-60 wt. % for the gum; and 2-40 wt. % for fibre from vegetableleaves or fruits.
 18. Dietary fibre blend according to claim 15, 16 or17, comprising a fibre from an oil seed or nut, other than resistantstarch and gum.
 19. Dietary fibre blend according to any of the claims15-18, comprising a fibre selected from the group of polydextrose,fructooligosaccharides and galactooligosaccharides.
 20. Dietary fibreblend according to any of the claims 15-19, wherein the gum is partiallyhydrolysed, and at least 60 wt. % of the gum has a degree ofpolymerization in the range of 3-10.
 21. Food product comprising adietary fibre blend according to any of the claims 15-20.
 22. Apharmaceutical composition comprising a (i) drug having an inhibitoryaction on serotonin reuptake, an inhibitory action monoamino oxidation,or an opiate; (ii) a dietary fibre or dietary fibre blend; and (iii) apharmaceutically acceptable excipient, wherein the dietary fibre ofdietary fibre blend is as defined in any of the claims 1-21.
 23. Amedical food product having an energy density of more than 1.67 kJ pergram, the composition comprising dietary fibre or dietary fibre blend asdefined in any of the preceding claims in a total relative amount of atleast 0.7 g/100 g dietary fibre, and less than 10 g/100 g protein. 24.Medical food product according to claim 23, wherein the product is afluid.
 25. Medical food product according to claim 23 or 24, comprisingup to 4 g/100 g lipid, preferably in an amount providing 1-35 en % ofthe total energy density of the product.
 26. Medical food productaccording to any of the claims 23-25, comprising a lipid fraction, saidlipid fraction providing 2-70 g octanoic acid per 100 g fatty acids. 27.Medical food product according to any of the claims 23-26, comprisingrice fibre, preferably rice bran, in particular rice bran combined withrice germ.
 28. Medical food product according to any of the claims23-27, wherein the product comprises a tryptophan source.
 29. Medicalfood according to any of the claims 23-28, wherein the medical food hasless than 0.3 g per 100 ml added organic acids, preferably less than0.26 g, more preferably 0.02-0.18 g/100 ml.
 30. Medical food accordingto any of the claims 23-29, wherein the glutamine content in the proteinfraction is less than 10 g per 100 g protein, preferably—9 g per 100 gprotein fraction.
 31. Packaging, in particular a unit-dose packaging,comprising 5-300 g, preferably 12-130 g of a liquid or semi-solid foodproduct according to any of the claim 18 or 20-26.
 32. Packaging, inparticular a unit-dose packaging, comprising 0.5-10 g of a solid foodproduct according to any of the claim 18 or 20-26.
 33. Kit of partscomprising at least two separately packaged components, wherein at leastone component comprises a dietary fibre as defined in any of the claim2-11, or 14 or a dietary fibre blend according to any of the claims15-19, and wherein the at least one other component comprises an opiate,a drug having an inhibitory action on serotonin reuptake, a drug havingan inhibitory action on monoamino oxidation in humans, or a medical foodproduct.
 34. Method for prophylactically or therapeutically treating ahuman in need thereof, the treatment comprising administering aneffective amount of a dietary fibre or dietary fibre blend, incombination with a pharmaceutical composition or a nutrition as definedin any of the preceding claims, thereby reducing a sating effect of thepharmaceutical composition or the nutrition.
 35. Method according toclaim 34, wherein the human in need thereof, is a human having an age ofat least 1 years, in particular a human having an age of at least 2years.
 36. Method according to any of the claim 34 or 35, wherein thedietary fibre and the pharmaceutical composition or nutrition isadministered orally or administered into the gastrointestinal tractthrough a tube.